Nongenomic Actions of Thyroid Hormone: The Integrin Component
Abstract
The extracellular domain of plasma membrane integrin αvβ3 contains a cell surface receptor for thyroid hormone analogues. The receptor is largely expressed and activated in tumor cells and rapidly dividing endothelial cells. The principal ligand for this receptor is l-thyroxine (T4), usually regarded only as a prohormone for 3,5,3′-triiodo-l-thyronine (T3), the hormone analogue that expresses thyroid hormone in the cell nucleus via nuclear receptors that are unrelated structurally to integrin αvβ3. At the integrin receptor for thyroid hormone, T4 regulates cancer and endothelial cell division, tumor cell defense pathways (such as anti-apoptosis), and angiogenesis and supports metastasis, radioresistance, and chemoresistance. The molecular mechanisms involve signal transduction via mitogen-activated protein kinase and phosphatidylinositol 3-kinase, differential expression of multiple genes related to the listed cell processes, and regulation of activities of other cell surface proteins, such as vascular growth factor receptors. Tetraiodothyroacetic acid (tetrac) is derived from T4 and competes with binding of T4 to the integrin. In the absence of T4, tetrac and chemically modified tetrac also have anticancer effects that culminate in altered gene transcription. Tumor xenografts are arrested by unmodified and chemically modified tetrac. The receptor requires further characterization in terms of contributions to nonmalignant cells, such as platelets and phagocytes. The integrin αvβ3 receptor for thyroid hormone offers a large panel of cellular actions that are relevant to cancer biology and that may be regulated by tetrac derivatives.
Thyroid hormone as l-thyroxine (T4) acts at its plasma membrane receptor on integrin αvβ3 on cancer cells and on dividing endothelial cells to activate specific signal transduction systems and intracellular protein trafficking. The trafficking and activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) protein culminate in specific gene expression related to cell proliferation and to cell defense mechanisms, i.e., anti-apoptosis. Proteins driven to the nuclear compartment from cytoplasm by T4 include nuclear thyroid hormone receptors (TRs, such as TRβ1), estrogen receptor-α (ERα), and apoptosis-relevant p53. T4 acts at physiological concentrations at the thyroid hormone receptor on αvβ3, whereas actions of 3,5,3′-triiodo-l-thyronine (T3) at the integrin require supraphysiological levels. Actions of T3 are primarily expressed via nuclear TRs.
I. THYROID HORMONE RECEPTORS: INTRODUCTION
The anatomic and functional compartments of the cell are the nucleus, cytoplasm, cytoskeleton, organelles (mitochondria, endoplasmic reticulum), and plasma membrane. Each contains one or more proteins that bear specific thyroid hormone binding sites (receptors). “Thyroid hormone” may be 3,5,3′-triiodo-l-thyronine (T3), l-thyroxine (T4), or certain other thyroid hormone metabolites, such as tetraiodothyroacetic acid (tetrac) (FIGURE 1). Protein “receptors” bind thyroid hormone analogues with high affinity and initiate or mediate specific hormonal effects (8, 38, 65). T3 is the principal form of thyroid hormone that acts at nuclear receptors (TRs) (25, 38). A plasma membrane receptor for thyroid hormone, structurally unrelated to TRs, is the subject of this review. Its primary ligands are T4 and tetrac, hormone analogues that have antithetic effects at the cell surface (38, 65).
FIGURE 1.Molecular structures of thyroid hormone analogues 3,5,3′-triiodo-l-thyronine (T3), l-thyroxine (T4), tetraiodothyroacetic acid (tetrac), and 3,3′,5′-triiodo-l-thyronine (reverse T3, rT3). T3 is the modulator of genomic actions of thyroid hormone via intranuclear thyroid hormone receptor proteins (TRs). Much of T3 outside the thyroid gland originates from peripheral (non-thyroid) tissue deiodination of T4. T4 mediates many nongenomic actions of thyroid hormone at the plasma membrane integrin αvβ3 receptor that is the subject of this review. The integrin thyroid hormone receptor is structurally unrelated to TRs. Tetrac inhibits actions of T4 at αvβ3 and has actions at the integrin in the absence of T4. rT3 has been thought to be biologically inactive, but it has been shown to have actions at the integrin.
Within the cell, thyroid hormones may move among compartments (trafficking), e.g., TRs for T3 may move from cytoplasm to the nucleus under the direction of T4 at the plasma membrane (32, 71, 160), bind nuclear T3 and modulate—in conjunction with co-activator or co-repressor proteins—the transcription of specific genes. A component of a heterodimeric plasma membrane protein, integrin αvβ3, that contains a specific receptor for T4 may move to the cancer cell nucleus where it functions as a co-activator protein; this protein is monomeric αv (160), and its trafficking is promoted by T4. A modified nuclear TR protein (p30 TPα) may function in cytoplasm as a controller of the state of actin in the cell, namely, soluble versus fibrous actin (65). Despite the fact that the receptor in this action is a nuclear TR metabolite, it is T4 at a cell surface integrin that initiates the effect. This effect on action is a critical function in terms of structure and function of cells.
A substantial body of evidence testifies to the primary importance of intact nuclear TR proteins and their primary ligand, T3, in normal cells (38). The purpose of the current review, however, is to examine the multiple roles throughout the cell of the plasma membrane receptor for T4 on integrin αvβ3. It is critical to point out that it is in cancer cells (61, 153, 190) that the actions of the thyroid hormone analogue receptor on αvβ3 are largely expressed. Cancer cell proliferation, the defense pathways of cancer cells—for example, anti-apoptosis mechanism—and control of tumor-relevant angiogenesis are regulated by T4 at the integrin (38, 65). Differential regulation by T4 may also be initiated at the integrin of driver genes and genes relevant to cell metabolism/respiration (ATP synthesis) (64). In addition to this substantial panel of effects on tumor cells, T4 at integrin αvβ3 may also affect functions in specialized, nonmalignant cells. Such cells include phagocytes (36) and developing prefrontal brain cortex sensory neurons (279). Function of the cell-like platelet may also be directed from αvβ3 (195). Normal angiogenesis (191), as well as new blood vessel formation linked to cancer cells, is stimulated by T4. Such functions are also examined in the discussions below.
A. Nuclear Thyroid Hormone Receptors
The genomic actions of thyroid hormone directed by T3-nuclear TR complexes in conjunction with co-activator and co-repressor proteins are extensively reviewed elsewhere (38, 252). Complexes of TRα and -β isoforms with T3 in the cell nucleus are transcriptionally active when bound by thyroid hormone response elements of thyroid hormone-responsive genes. Transcription may be modified by simultaneously bound co-activator and co-repressor proteins. This paradigm prevails in normal (nonmalignant) cells and may be operative to a more limited extent in tumor cells, where the cell surface thyroid hormone receptor on integrin αvβ3 may dominate control of transcription (61, 65), as will be discussed below.
The overlapping of genomic and nongenomic actions of the hormone has also been emphasized recently (107). Transcription of the TRβ1 gene can be regulated from integrin αvβ3 by T4 (160), but the primary ligand of the gene product is T3. The αv monomer component of plasma membrane αvβ3 can migrate to the nucleus of tumor cells to serve as a co-activator for expression of specific genes (see sect. IC). The trafficking of TRβ1 from cytoplasm to nucleus may be directed by T4 at the integrin (71).
B. Cytoplasmic Thyroid Hormone Receptors
Iodothyronine trafficking through cytoplasm is of course essential to nuclear uptake and mitochondrial actions of the hormones. A number of reports have documented binding of iodothyronines by proteins in cytoplasm (38). Certain of these proteins are nuclear TRs that shuttle between cytoplasm and nucleus (38, 67), e.g., TRβ1 and a truncated TRα1 (TRΔα1). The latter is involved in regulation of the state of actin (soluble vs. fibrous) in cytoplasm and is critical to cell mobility and cell shape. Other specific proteins identified to bind thyroid hormone in cytoplasm include µ-crystallin (ketimine reductase; NADPH) (106, 245), a protein involved in certain sensory functions in neurons and in lysine degradation (106), and thyroxine-binding globulin (TBG) or a TBG-like protein in breast adipose tissue (215), the function of which was not identified. Pyruvate kinase (p58) monomer in cytoplasm binds T3, and such binding inhibits enzyme activity of the protein (131, 200). Compared with pyruvate kinase tetramer, the monomer has relatively low enzyme activity, but it is speculated to be involved in cell metabolism because T3 inhibits conversion of p58 to the tetrameric form (131).
Unidentified cytoplasmic iodothyronine-binding proteins (CTBP) have been described in developing brain cortex and cerebellum (145) and disappear with brain maturation. Myocardial cytoplasm has also been reported to contain a protein that binds T4 and reverse T3 (rT3; 3,3′,5′-triiodo-L-thyronine; FIGURE 1) in a Ca2+-dependent manner (15). It is also of interest that hemoglobin in erythrocyte cytosol binds thyroid hormone (281, 282). Regrettably, the exact nature and function of these binding moieties in brain, heart, and red blood cells were not pursued.
C. Regulation of the Cellular State of Actin by Thyroid Hormone
The control by T4 and rT3, but not T3, of the state of actin in cells has been extensively explored by Leonard and Farwell in neurons (38, 92). The importance of this finding relates to regulation by specific thyroid hormone analogues of intracellular structural organization, relative mobility of cells and cell-cell interactions, as well as organ development.
The physical linkage of actin to αvβ3 modulates cell adhesion/cell mobility (68, 100, 246), and the state and/or function of both proteins is under the control of T4. A contribution of T4 to intracellular organization and functions such as specific protein trafficking [TRs, estrogen receptor (ER)α] and signal transducing kinases thus occurs not only via action of the hormone on the state of actin, but also on the communication between αvβ3 and actin.
Stabilization of the actin cytoskeleton in T4-exposed tumor cells via αvβ3 also facilitates the T4-directed translocation of monomeric αv to the nucleus where it functions as a co-activator for expression of cyclooxygenase-2 (COX-2) and hypoxia-inducible factor-1α (HIF-1α) genes and the ERα gene (160).
D. Cell Surface Membrane Receptor for Thyroid Hormone on Integrin αvβ3
The plasma membrane receptor for thyroid hormone analogues on the extracellular domain of integrin αvβ3 was described in 2005 (19). In contrast to TRs that function genomically in the nucleus, the cell surface receptor was found, when liganded to certain iodothyronines, to activate signal transduction systems that were capable of modulated local plasma membrane functions (such as ion transporter), to control specific intracellular protein trafficking (such as that of TRs and ΕRα) and to regulate differentially the transcription of a large number of genes important to tumor cell function (38, 61, 65). T4 and tetrac act at the plasma membrane receptor to control expression of genes linked to regulation of cell division, to cancer cell survival pathways, and to angiogenesis (38, 61, 65, 102). Previously viewed as an inactive hormone analogue, rT3 (FIGURE 1) may act at the cell surface to promote cancer cell proliferation (77, 165) (see sect. XIVA).
Ion transporter genes capable of responding in tumor cells to thyroid hormone at the cell surface are important to regulation of extracellular pH, e.g., the Na+-H+ exchanger (163, 235). The P-glycoprotein (P-gp) pump gene was also found to be susceptible to regulation from αvβ3 by thyroid hormone, and this is important to export of chemical molecules, such as chemotherapeutic agents. Regulation of extracellular pH may also affect the susceptibility of chemotherapeutic agents to uptake by cancer cells (163).
The integrin is expressed to a lesser extent by nonmalignant cells and by platelets (195). Here, however, the functions of the thyroid hormone analogue receptor do not appear to include regulation of cell division (see sect. IIIG) or apoptosis, but are linked to developmental functions (such as neuronal currents in developing brain), to normal angiogenesis, and in the case of the platelet, to aggregation and clotting (73, 195).
FIGURE 2 is an overview of the induction pathways to functions of the αvβ3 thyroid hormone receptor in cancer cell and rapidly dividing endothelial cells. Actions of T4 at the receptor have consequences in terms of intracellular protein trafficking, nucleoprotein phosphorylation, specific gene transcription, mitochondrial respiration, and control of the state of actin.
FIGURE 2.Nongenomic actions of thyroid hormone primarily as l-thyroxine (T4) that are initiated at the tumor cell surface. These include intracellular protein trafficking, e.g., driving of cytoplasmic thyroid hormone receptor proteins (TRs), estrogen receptor-α (ERα), mitogen-activated protein kinase (MAPK; ERK1/2), and signal transducer and activator of transcription (STAT) proteins into the nucleus, specific serine phosphorylation of nucleoprotein hormone receptors, thus influencing specific gene transcription and p53. Nongenomic actions of T4 at the cell surface also involve regulation of ion transporter and P-glycoprotein (P-gp) transporter activities. The state of intracellular actin (soluble vs. fibrous) is regulated by T4, but it is not known where these actions are initiated. These actions are discussed in detail in various later sections of this review. Structural aspects of the thyroid hormone receptor of integrin αvβ3 are found in section III. [Modified from Davis et al. (68), with permission from Elsevier.]
The primary ligand of nuclear TRs is T3, as noted above, and hormone analogues such as T4 and tetrac have very limited thyromimetic activity (38). T4 has an important role vis-à-vis TR in that it is a prohormone for T3. At the thyroid hormone receptor on αvβ3, however, T4 at physiological levels is the primary ligand and thus is capable of supporting tumor growth. T4, but not T3, in physiological concentrations has been shown in a variety of preclinical studies (160, 162) and in limited clinical evidence to contribute to tumor aggressiveness (111, 113).
Tetrac has extraordinary activity at the integrin; it is capable of blocking T4 binding to the receptor, but in the absence of T4 differentially controls transcription of a number of genes that are tumor-relevant (61, 102). The consequence is that tetrac and certain chemical modifications of tetrac, such as a nanoparticulate form (20, 40, 194, 241, 274, 275), can inhibit tumor cell division and block angiogenesis (76). The gene specificity of actions of tetrac and nanoparticulate tetrac initiated at αvβ3 are remarkable (61, 102), as discussed elsewhere in this review. Expression of the genes for the monomers that make up heterodimeric αvβ3 is also regulated from the thyroid hormone analogue receptor.
Integrins are highly plastic (10, 228), and the binding of tetrac can prevent αvβ3 from being activated, e.g., by radiation (142). Integrins are known primarily for abilities to bind to ligand extracellular matrix (ECM) proteins, such as vitronectin and fibronectin. The fact that αvβ3 has a binding site for thyroid hormone analogues and sites for other small molecules (163) is providing new insights into the functions of the integrin. But it also has fostered studies recognizing the control by thyroid hormone binding at the integrin to alter the interactions of αvβ3 with adjacent cell surface large molecules, such as the receptors for vascular endothelial growth factor (VEGF) and basic fibroblast growth factor [bFGF or fibroblast growth factor 2 (FGF2)]. Changes in the nature or degree of integrin-VEGF receptor (VEGFR) or integrin-bFGF interactions can stimulate or inhibit angiogenesis (76, 188), depending on whether T4 or tetrac is the ligand. Hormone binding by αvβ3 can also change the manner in which the integrin interacts with ECM proteins, such as vitronectin (76).
Finally, the intracellular trafficking of the αv monomer of αvβ3 is regulated by T4 at the receptor on the integrin. In the cell nucleus, αv is a co-activator protein for expression of certain genes (160).
II. OVERVIEW OF INTEGRIN FAMILY
A. Structure of Integrins, Location in Cells, Extracellular Matrix Protein Ligands, Integrin Functions, Specific Functions ofαvβ3
1. Structure of integrins
Integrins are large, trans-plasma membrane proteins that are essential to cell-cell interactions and thus to tissue structure. As noted above, they are cell adhesion molecules (122, 123) that bind to extracellular matrix ligands, cell-surface ligands, and soluble protein (extracellular matrix) ligands (248). One of the two dozen integrins, αvβ3 has been recognized recently to have small molecule, naturally occurring ligands, namely, thyroid hormone analogues and steroids (42, 65, 163). As noted in section I, another feature of most integrins is the capacity to bind specifically a panel of discrete ligands. These typically are proteins, but αvβ3 has been shown to bind small molecules, such as resveratrol (41, 158), dihydrotestosterone (42, 161), and the thyroid hormone analogues that are discussed throughout this review (65). The liganding of each of these categories of small molecules results in specific intracellular events or in local actions in the plasma membrane.
Integrins are heterodimers consisting of an α chain and a β chain that are noncovalently linked. Each monomer features a large extracellular domain and a usually short cytoplasmic domain. Mammalian integrins are the result of 18 α-subunit genes and 8 β-subunit genes. In place in the plasma membrane, integrins adopt a shape resembling a “head” on two “legs.” The head includes sites for ligand binding (31). Cytosolic domains of integrin coordinate assembly of the cytoskeleton polymers and downstream transduction networks for extracellular and cell surface source signals. These linkages function bidirectionally, coordinating interactions of the cellular microenvironment and the immediate extracellular/intercellular space. Integrins have been shown to play vital roles in tissue integrity, cell trafficking, and differentiation (22, 24).
The structure of integrins is highly plastic (FIGURE 3), and αvβ3 has been well-studied in this regard (10). Liganding of molecules and certain physical influences, such as radiation (142), may alter the conformation of the heterodimer and alter its function state (“activation”). The T4 analogue tetrac is a ligand of the head of αvβ3 and reverses the radiation-activation of the integrin (142). This activation of the protein is thought to relate to radioresistance. Other factors influencing the activation of various integrins have recently been reviewed (244).
FIGURE 3.Depiction of the plasticity of an integrin such as αvβ3. The conformations of the heterodimer are, left to right, extended open, extended closed, and fully closed, bent. Principal liganding sites for extracellular matrix proteins and for small molecules such as thyroid hormone analogues are on the interacting “heads” of the αv and β3 monomers (left configuration). Structural contributions to the thyroid hormone receptor site come from each monomer and T4 will not bind to αv or β3, alone (160). Thyroid hormone analogues are factors controlling the conformations of the integrin shown here (see sect. IIIC) (142, 143), particularly in cancer cells. By specific anatomic changes secondary to extracellular component integrin conformational alterations, the intracellular (cytoplasmic) components of the monomers (“feet”) interact with and modulate the activity of signal transduction pathway components, such as MAPK and STAT (shown in FIGURE 2 and discussed in sect. III). Acting via the integrin, T4 regulates intracellular trafficking of a number of proteins, including cytoplasm-to-nucleus transfer of thyroid hormone receptors, estrogen receptor, and monomeric αv (see sect. V). The closed configuration is thought to obscure the thyroid hormone receptor on the head of the integrin.
Posttranslational modification of integrins has been reported. For example, integrin αvβ3 is phosphorylated after thyroxine binding (160). N-glycosylation sites exist on αvβ3 (17), and thyroid hormone analogues are known to glycosylate certain proteins, such as tissue plasminogen activator (99). However, iodothyronine-stimulated glycosylation has not yet been studied in integrins.
2. Location of integrins in cells
The subcellular location of integrins and integrin subunits and the receptors they bear pertain importantly to cell function and protein trafficking. Subunit α3A is a well-studied example, delimiting focal contacts in several cell types cultured on fibronectin, kalinin/laminin 5, EHS-laminin/laminin 1, type IV collagen, or vitronectin, indicating that the cytoplasmic domain is hidden in intact focal contacts by cytoskeletal or other cytoplasmic proteins (85). Thyroid hormone analogues are not known to affect α3A, but the subcellular location and certain functions of αv monomer are regulated by T4 (160). αv has been identified in certain cell contact sites (85), and it would be useful to determine whether the hormone regulates contact site interaction of tumor cells with extracellular matrix proteins and contact site links to intracellular proteins.
Other integrins and monomers such as α3β1 and α6β1 localize in tumor cells (56, 237) and contribute to the metastatic process. Thyroid hormone appears to enhance metastasis (190), but it has not been determined whether this contribution depends on regulation by the hormone of intracellular locations of integrins and integrin monomers other than αv. Moreno-Layseca et al. (186) have examined the cellular trafficking of integrins in normal cells.
3. Extracellular matrix protein ligands
Integrins can transmit ECM-integrin signaling to regulate different cellular activities for cell survival and movement. It has been considered that integrin signaling occurs fully from adhesion sites at the plasma membrane (3) or from endosomes. In germline competent rat embryonic stem cells (rESCs), laminin is a crucial component in the differentiation of rESCs into cardiomyocytes through increasing their proliferation via interacting with integrin pathway mediated by extracellular laminin involved in the fate of rESC-derived cardiomyocytes (263). Integrin can interact with laminin to induce phosphorylation of both phosphatidylinositol 3-kinase (PI3K) p85 and focal adhesion kinase (FAK) (263). Tight junction formation and apicobasolateral polarization can be induced by adding polymerized superfibronectin, which can be induced by specific integrin β1 activating antibody (237).
Studies of integrins and ligands in ECM in trophoblasts at the maternal-fetal interface during tubal pregnancy reveal an early relationship. Fibronectin, laminin, and type IV collagen can be detected in column cytotrophoblastic cells (CTB) and some invasive extravillous cytotrophoblast (EVCT) cells, and the alterations are coincident with those of the corresponding integrin receptors in EVCT cells (210).
4. Integrin functions
Functions of integrins have been revealed by studies from cell biology and genetic analyses. Genetic analyses of engineered or natural mutations have further confirmed key roles for integrins in tissue integrity, cell trafficking, and differentiation (22, 24).
Integrins mediate cell-cell, cell-ECM, and cell-pathogen interactions. They can bind with ligand to transduce signals from the extracellular domain to the cytoplasm in the classical outside-in direction (170). Additionally, a characteristic feature of most integrin receptors is their ability to bind various different ligands. Conversely, several ECMs and cell surface adhesion proteins have been shown to bind with different integrin receptors (122, 207, 261). Integrins also play vital roles in the immune system for leukocyte trafficking and migrating, immunological synapse formation, co-stimulation, and phagocytosis (117, 219). Dynamically, integrin can perform cell adhesiveness via inside-out signaling process (230).
Overexpressed integrins present on the surface of cancer cells or stromal cells mediate cell-matrix adhesion, which may promote survival capability of those cells in the specific location (5). Interactions between cancer cells and their microenvironment can trigger essential signaling that decide cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell-matrix adhesion, integrins that are present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations. However, these integrin receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses (228).
Integrin cytosolic domains coordinate the assembly of cytoskeletal polymers and signaling complexes in the cytosol. Alternatively, extracellular domains of integrins connect either ECM macromolecules or counter-receptors on adjacent cell surfaces. These bidirectional linkages impose spatial restrictions on signaling and ECM assembly. Therefore, integrins integrate cells with their microenvironment. Sequentially, membrane-proximal interactions initiate more distal functions such as tissue patterning (extracellularly) and cell fate determination (intracellularly). Integrin-mediated FAK signaling is strongly dependent on integrin endocytosis, and endosomal FAK signaling facilitates cancer metastasis by supporting anchorage-independent growth and anoikis resistance (3). In addition, activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 has also been reported to be involved in activities of integrins. Surrounding a wound, integrins rapidly accumulate in a c-Jun NH2-terminal kinases (JNK)-dependent manner in a few rows of cells. Interestingly, the integrins localize to the distal margin in these cells, instead of the frontal or lamellipodial distribution expected for proteins providing traction and recruit nonmuscle myosin II to the same location (204). Signaling roles of integrins may be important for epithelial polarization around wounds (204).
Apicobasolateral polarity is a fundamental property of epithelial cells, and its loss is a hallmark of cancer (237). Addition of an integrin β1-activating monoclonal antibody, P4G11, to invasive colorectal cancer cells in three-dimensional type 1 collagen reverts the invasive phenotype and restores apicobasolateral polarity. However, inducible elimination of integrin α5 abrogates the epithelial-organizing effects of β1-activating monoclonal antibody, P4G11 (237).
Glioblastoma (GBM) is the most lethal primary brain tumor in adults and is known to be particularly aggressive and resistant to anticancer therapies, mainly due to the presence of GBM stem cells (GBMSC). Integrin α6 regulates the expression of fibroblast growth factor receptor 1 (FGFR1) and its target gene Forkhead Box M1 (FOXM1) via the ZEB1/YAP1 transcription complex in GBM cells. Integrin α6 and FGFR1 work in concert to regulate proliferation and stemness of GBMSC. Co-administration of anti-FGFR1 and anti-integrin α6 could provide an improved therapeutic response in GBMSC (133).
GATA4, which is a critical transcription factor for proper mammalian cardiac development and essential for survival of the embryo, is upregulated. Upon inhibiting the integrin, laminin loses the effect on cardiomyocyte differentiation, accompanied with a downregulation of phosphorylation level of PI3K p85 and FAK. Meanwhile, the expression of GATA4 is inhibited as well. Integrin-mediated contact with the ECM defines the basal surface, setting in motion E-cadherin-mediated cell-cell contact, which establishes apicobasolateral polarity that is a fundamental property of epithelial cells, and its loss is a hallmark of cancer (237).
Laminin is stained dominatingly in extravillous cytotrophoblasts invading maternal blood vessels and deep into the interstitium. Maternal epithelial, endothelial, and stromal cells also express integrin subunits α1, β1, α5, and heterodimer α5β1 and ECM ligands, indicating involvement in mediating the adhesion of trophoblasts to the epithelium of the maternal fallopian tube (196). The increased expression of integrins and their ligands in column CTB and invasive EVCT cells may also facilitate the invasion of trophoblasts into the maternal interstitium. Moreover, trophoblasts possessed the potential for self-controlled adhesion and invasion and appear to reach peak invasive capability in the second month of tubal implantation (210).
Exposure of primate kidney epithelial BS-C-1 cells to nonlethal oxidative stress results in the disruption of focal contacts, disappearance of talin from the basal cell surface, and redistribution of integrin α3 from predominantly basal location to the apical cell surface. Oxidative stress decreases BS-C-1 cell adhesion to type IV collagen, laminin, fibronectin, and vitronectin; however, defective adhesion is not associated with a loss of integrin subunits α3, α4, or αv from the cell surface (98).
Hematopoietic stem cells (HSCs) are the vital, life-long source of all blood cell types found in stem cell niches (26). The specific anatomic locations offer all the factors and signals necessary for the maintenance of the stem cell potential of HSCs (217, 277). HSCs proved to be sensitive to the lateral distance between the presented ligands with regard to adhesion and lipid raft clustering, the latter being a prerequisite for the formation of signaling complexes. Furthermore, an extensive redistribution of stem cell markers, integrins, and phosphorylated proteins in HSCs occurs. Integrin-mediated adhesion and signaling of HSCs proved to depend on the nanostructured presentation of ligands in their environment (7).
Although studies indicate that integrin α3β1 is a receptor for a variety of extracellular ligands, reports of α3β1-ligand interactions are inconsistent. Transfection studies have suggested that α3β1 is not sufficient for cell attachment to ligands other than kalinin/laminin 5. On the other hand, α3Aβ1 responds to a broad spectrum of extracellular ligands. Time course comparisons of the recruitment of α subunits from different fibronectin receptors indicate that localization of α3Aβ1 to fibronectin-induced focal contacts is independent of the recruitment of α5 and α4 integrins (85). However, other studies have shown that α3Aβ1 does not mediate initial cell adhesion to many of the ligands that induced its focal contact localization, including fibronectin. Therefore, α3Aβ1 may be a secondary receptor with post-cell-adhesion functions for a broad spectrum of extracellular matrices (85).
During pregnancy, the trophoblast cells of the placenta are the only fetal cells in direct contact with maternal blood and decidua. Their functions include transport of nutrients and oxygen, secretion of pregnancy hormones, remodeling of the uterine arteries, and communicating with maternal cells. A proliferative trophoblast niche at the base of the cytotrophoblast cell columns in first trimester placentas is characterized by integrin α2 (ITGA2) expression (138).
GGA3 knockdown reduces cell surface and total levels of α2, α5, and β1 integrin subunits; inhibits cell spreading; and reduces focal adhesion number as well as cell migration. In the absence of GGA3, integrins are increasingly retained inside the cell and trafficked toward the perinuclear lysosomal compartment, and their degradation is enhanced. Integrin traffic and maintenance of integrin levels are dependent on the integrity of the Arf binding site of GGA3. Furthermore, sorting nexin 17 (SNX17), a critical regulator of integrin recycling, becomes mislocalized to enlarged late endosomes upon GGA3 depletion. These data support a model whereby GGA3, through its ability to regulate SNX17 endosomal localization and through interaction with Arf6, diverts integrins from the degradative pathway supporting cell migration (216). A novel role for integrin α5β1 is in regulating epithelial morphogenesis (237).
Atherosclerosis occurs preferentially at the blood vessels encountering blood flow turbulence. Matricellular protein CCN1 induces atherosclerosis via modulating endothelial phenotypes. CCN1 binds to its receptor integrin α6β1 to activate nuclear factor (NF)-κB, thereby instigating a vicious circle to persistently promote atherogenesis. The matricellular protein CCN1 is induced in endothelial cells by disturbed flow and is expressed in advanced atherosclerotic lesions in patients and in the Apoe−/− mouse model (121). A selective antagonist, T1 peptide-targeting CCN1-α6β1, can be further optimized for developing T1-mimetics to treat atherosclerosis.
Studies suggest that neurons can regulate the ligand specificity of individual integrin heterodimers (e.g., α1β1). Integrin β1 heterodimers mediate attachment and neurite outgrowth in response to neurite-promoting ECM molecules in primary neurons and neuronal cell lines (257). Individual cells are likely to express several integrin α subunits with β1 subunit, each possessing unique ligand specificities. In some cases, a cell may express two β1 integrins that recognize different binding domains in a single ECM ligand, as appears to be the case for the α3β1 and α1β1 integrins on PC12 cells. Given the tremendous diversity in the ECM surrounding them, neurons possess intrinsic factors to dictate their responses to a particular ECM component (256). Thus the responses of a neuron to even a single ligand may be regulated by the combined action of several receptors (256). N-glycosylations can regulate the adhesive function of integrins (29).
5. Specific functions of αvβ3
Integrin αvβ3 expresses in various cancer cells, potent growth endothelial cells, and osteocytes. Integrin αvβ3 is required for cathepsin B-induced hepatocellular carcinoma progression (271). Specific antagonists to integrin subunit β3 block integrin αvβ3 activity in MLO-Y4 mouse osteocytes. Blocking integrin αvβ3 disrupts osteocyte morphology, causing a reduction in spread area and process retraction (109). Blockage of integrin αvβ3 also disrupts COX-2 expression and prostaglandin (PG) E2 release in response to fluid shear stress (109), suggesting that integrin αvβ3 is essential for the maintenance of osteocyte cell processes and also for mechanosensation and mechanotransduction by osteocytes (109). Our studies also indicate that resveratrol-induced nuclear accumulation of COX-2 and phosphorylated p53-COX-2-dependent anti-proliferation sequentially in cancer cells is via integrin αvβ3 signaling transduction pathway (153). In addition, integrin αvβ3 plays an important role in growth of leiomyomas (myomas), the most common benign smooth muscle cell tumor of the myometrium. Insulin-like growth factor (IGF) stimulates uterine fibroid via integrin αvβ3 crosstalk with IGF receptor (116); therefore, resveratrol can inhibit uterine fibroid growth directly or inhibit IGF activity (116).
B. Small Molecule Ligands of αvβ3: Stilbenes, Androgen, Thyroid Hormone Analogues
There are several small molecules in addition to molecules with Arg-Gly-Asp (RGD) binding domain that have been shown to bind to integrin αvβ3 as receptor.
1. Stilbenes
Resveratrol induces anti-proliferation in different types of cancers. There are several mechanisms proposed in resveratrol-induced anticancer activities. The dynamic processes of the plasma membrane reveal the importance of the role of lipid composition in the fluidity, the lipid rafts in resveratrol endocytosis, and the ATP-binding cassette transporters in resveratrol efflux. Specific membrane receptors such as integrin αvβ3 contribute to resveratrol uptake and to activating signaling pathways involved in apoptosis (82). Principally, radiolabeled resveratrol accumulates in sphingomyelin- and cholesterol-enriched cell fractions. ERK, JNK, and Akt also accumulate in lipid rafts on resveratrol-exposed SW480 and U937 cells. Resveratrol binds to integrin αvβ3 to activate downstream ERK1/2 activation. In cell membrane lipid rafts, resveratrol promotes recruitment of integrin αvβ3 with signaling molecules including FAK, Fyn, Grb2, Ras, and SOS proteins (52). Resveratrol-induced activation of downstream signaling pathways and caspase-dependent apoptosis are prevented by endocytosis inhibitors, lipid raft-disrupting molecules, and the integrin antagonist RGD peptide. Altogether, these data show the role played by lipid rafts in resveratrol endocytosis and activation of downstream pathways leading to cell death. Activated ERK1/2 induces COX-2 expression. Inducible COX-2 translocates to nucleus with activated ERK1/2 and SUMO-1. Nuclear COX-2-activated ERK1/2 complex associates with p53 and induces p53 phosphorylation. The phosphorylated p53 complex further activates expression of p53-responsive genes (157). Resveratrol derivative, triacetyl-resveratrol, induces both ERK and p38 phosphorylation via integrin αvβ3 to activate p53-dependent anti-proliferation (120). In contrast, binding of trimethoxy-resveratrol to integrin αvβ3 was substantially less robust (120). Belleri et al. (18) have shown recruitment of enhanced green fluorescent protein-tagged β3 integrin in focal adhesion contacts. In addition, trans-resveratrol, but not cis-resveratrol, inhibits integrin αvβ3-dependent endothelial cell adhesion, and in vivo, trans-resveratrol inhibits vascularization of the chick embryo area vasculosa and murine melanoma B16 tumor growth and neovascularization. cis-Resveratrol employs a limited, if any, effect. The observation suggests that stereoisomerism affects the anti-angiogenic activity of resveratrol, with the trans isomer being significantly more potent than the cis isoform. The different anti-angiogenic potential of resveratrol stereoisomers is related, at least in part, to their different capacity to affect αvβ3 integrin function (18). Leiomyomas (myomas) are the most common benign smooth muscle cell tumor of the myometrium. Resveratrol arrested cell proliferation via integrin αvβ3 (116). However, other studies indicate that resveratrol decreases cellular α5β1 integrin level in ovarian cancer cells. The resveratrol-induced decreased functionality corresponds with reduced efficiency of cancer cell adhesion (181).
2. Androgen
Androgen binds to its nuclear androgen receptor in cytoplasm. Ligand-receptor complex translocates to nucleus, binding with promoters of androgen-responsible genes. Androgen stimulates androgen-sensitive prostate cancer cell proliferation. However, our studies indicate that androgen, dihydrotestosterone (DHT), can stimulate growth in both estrogen-sensitive and -insensitive breast cancer cells. In addition to binding to ERα in ER-positive breast cancer cells, the DHT membrane receptor exists on integrin αvβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin αvβ3. In human-derived PC3 prostate cancer cells isolated from bone metastasis, coordination between Smad 5 phosphorylation induced by integrin αvβ3 signaling and RUNX2 phosphorylation by CD44 signaling regulates RANKL expression (105). RUNX2 intranuclear targeting is mediated by phosphorylation of Smad 5. CDK11(p58), a Ser/Thr kinase that belongs to the cell division cycle 2-like 1 (CDC2L1) subfamily, is associated with cell cycle progression, tumorigenesis, and apoptotic signaling. It is capable of repressing the migration and invasion of ERα-positive breast cancer cells, but not ERα-negative breast cancer cells, in a kinase-dependent manner (39). Gene expression assays demonstrated that integrin β3 mRNA was dramatically repressed by CDK11(p58), and luciferase results confirmed that integrin β3 promoter was inhibited by CDK11(p58) through ERα repression. Expression of integrin β3 was highly related to ERα signaling; ERα overexpression stimulated integrin β3 expression (39). Androgen-independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior (185). We have previously shown that gonadotropin releasing hormone (GnRH) agonists exert a direct and specific inhibitory action on the proliferation of androgen-independent prostate cancer cells (DU 145). GnRH agonist Leuprolide abolishes the effects of IGF-I on cell morphology, on actin cytoskeleton organization, and on αvβ3 integrin expression/cellular localization (185). Orphan nuclear receptors constitute a subgroup of the superfamily of steroid/thyroid/retinoid receptors for which no endogenous ligand has been identified. The orphan nuclear receptor RORα has been shown to be involved in the control of cell growth and differentiation. RORα activation resulted in a decreased expression of integrin αvβ3 and an increased level of expression of integrin subunit β4 (187).
3. Thyroid hormone analogues
In addition to nuclear thyroid hormone receptors, thyroid hormones can bind to receptor on cell surface integrin αvβ3 (153). There is one integrin αvβ3 receptor (S2) for T4 and two integrin αvβ3 receptors (S1 and S2) for T3 (60, 65, 162). Physiological concentration of T4 (total T4 concentration, 10−7 M; free T4 concentration, 10−10 M), but not T3 binds to integrin αvβ3, to induce cellular internalization and nuclear translocation of the integrin αv monomer in cancer cells. T4-induced activated ERK1/2 phosphorylated αv monomer of internalized integrin αvβ3 has been demonstrated when it heterodimerizes with integrin β3 in vitro. The phosphorylated αv monomer, leaving β3 monomer behind, translocates to nuclei. The nuclear αv monomer complexes with certain nuclear factors such as transcriptional co-activator proteins, p300, signal transducer and activator of transcription (STAT)1, and with the co-repressor proteins NCoR and SMRT. The nuclear αv monomer complex in T4-exposed cells is bound to promoters of T4-responsive genes that have important roles in cancer cells such as ERα, COX-2, HIF-1α, and TRβ1.
Endocytic trafficking of heterodimeric integrins and their recycling to the cell surface has been well-characterized (186). It is not yet known whether cell uptake of monomeric integrin αv from αvβ3 in response to T4 involves factors such as specific GTPases or clathrin that can be relevant to uptake of dimeric integrins.
III. STRUCTURAL FEATURES OF THYROID HORMONE RECEPTOR ON INTEGRIN αvβ3 AND RELATIONSHIPS TO FUNCTION
A. Structure/Activity Features of Thyroid Hormone Analogues at the Receptor
By using combined QM/MM study, Freindorf et al. (96) conducted computation modeling of thyroid hormone binding on integrin αvβ3. Because thyroxine binding on integrin αvβ3 can be blocked by RGD peptide, they postulated that the binding site of thyroxine may be near RGD crevice. They proposed two starting positions of thyroxine on integrin αvβ3 RGD binding domains. The different starting positions condition T4 binding modes involving flipping of the hydroxyl and amino ends of the hormone in the binding pocket. In one of the orientations, the phenolic ring is located at the interface between the αv and β3 monomers. In the other orientation, the 4-hydroxyphenyl ring sits in a deep pocket within the crevice between the monomers. However, the binding site of thyroxine is the same in both models, only changing orientation.
For the binding of T3 to the integrin, two binding sites have been modeled because of in vitro pharmacokinetic observations (162). However, T3 modelings are significantly different from that of T4. Iodines have been shown to enhance hormone-protein binding by virtue of their electronic as well as steric properties (44). Interestingly, a halogen-free thyroid hormone analogue, N-acetyl-4′-methoxy-3,5,3′-trimethyl-l-thyronine ethyl ester, has a molecular conformation resembling T3. The overall conformation is cisoid with twist-skewed diphenyl ether conformation and distal 3′-methyl group (44). The required conformational features of T3 persist when methyl groups are substituted for halogens. Such a molecule has a low binding affinity for the integrin, but retains rather high hormonal activity. This suggests that the number of iodines may affect the binding of thyroid hormone analogs to integrin αvβ3. The tyrosyl moiety is located on the Arg side chain of the circular RGD peptide in one mode of T3. The second mode of binding of T3 places the 4-phenol ring in a different binding pocket as observed with T4 (96). Tetrac exposes another change in the binding mode. One of the tetrac orientations is associated along the side chain of Arg in the RGD peptide binding site, as observed for one orientation of T3. Comparing another starting position of T3 and tetrac reveals a binding mode in which the phenolic ring of tetrac binds deeper in the RGD binding pocket, similar to T4. However, because tetrac does not have an amino group, it can bind deeper than T4 in the RGD crevice. The phenolic ring of T3 occupies an alternating pocket that is not occupied by T4 or tetrac. A starting position calculated for the non-iodinated thyroid analogue GC-1 binds in a similar manner to T3. Differences in potential binding patterns of thyroid hormones on integrin αvβ3 are consistent with studies that show that RGD peptides can block interaction between thyroid hormone analogs and integrin αvβ3. However, the inhibitory sensitivities to RGD peptide may be different among thyroid hormone analogs.
B. Subspecialization of the Receptor Site (Domains 1 and 2) for Thyroid Hormone on Integrinαvβ3
The integrin αvβ3 thyroid hormone binding site contains two thyroid hormone-binding domains, designated S1 and S2. Those two domains differentially translate signals of T4 and T3 (162) (FIGURE 4). T3 at physiological concentrations exclusively binds with domain S1 leading to activation of PI3K and downstream signal transduction pathways. In addition, T3 also binds with domain S2 to a lesser extent, ultimately to activate ERK1/2 signal transduction pathway (162). However, T4 only binds to domain S2 to a activate ERK1/2 signal transduction pathway. Activation of the oncogenic ERK1/2 pathway by thyroid hormones, primarily T4, via the S2 site of αvβ3 facilitates cell proliferation and inhibits apoptosis. Via αvβ3/S2, the thyroid hormone can activate ERK1/2 and induce expression of bFGF and promote angiogenesis, and it is also crucial for rapid tumor growth (57). The T4-activated ERK1/2 can phosphorylate αv monomer of the internalized integrin αvβ3 in vitro. The consequences of thyroxine-induced nuclear accumulation of nuclear integrin αv transcriptional complex are to enhance proliferation of a variety of tumor cells, e.g., ovarian cancer (119) and non-small cell lung carcinoma (160). T4 stimulates growth of other cancer cells (48, 58, 59, 139, 197), but involvement of integrin αv monomer has not yet been studied in such cells as a possible potentiator of thyroid hormone action.
FIGURE 4.Proposed pathways by which thyroid hormones promote U-87 MG cell proliferation and intracellular trafficking of the thyroid hormone receptors TRα and TRβ1. Two hormone-binding sites [site 1 (S1) and site 2 (S2)] are proposed within the iodothyronine receptor domain on integrin αvβ3. 3,5,3′-Triiodo-l-thyronine (T3) interacts with S1 to activate the phosphatidylinositol 3-kinase (PI3K) signal transduction pathway via Src kinase activation. Downstream consequences are shuttling of cytoplasmic TRα to the nucleus and transcription of the hypoxia-inducible factor-1α (HIF-1α) gene. T3-initiated action at S1 is inhibited by tetraiodothyroacetic acid (tetrac) and the Arg-Gly-Asp (RGD) peptide. Inhibition of PI3K activation by LY-294002 downstream of Src blocks TRα shuttling and HIF-1α transcription, and inhibition of Src kinase activation by PP2 prevents hormone activation of PI3K and consequent cellular actions. Proliferation of U-87 MG cells in response to T3 is unaffected by this pathway. l-Thyroxine (T4) and T3 both bind to S2 to cause mitogen-activated protein kinase (ERK1/2)-dependent U-87 MG cell proliferation, and this effect is blocked by the ERK1/2 inhibitor PD-98059. The T4 effect on cell proliferation is inhibited by both tetrac and RGD peptide, but the action of T3 on cell proliferation via S2 is inhibited only by tetrac. This may reflect allosteric changes in the integrin site that are distinctive for the liganding of T3 and T4. At S2, the disproportionate sizes of “T4” and “T3” reflect the greater effectiveness of T4 at this site in terms of TRβ1 trafficking and cell proliferation. [From Lin et al. (162). Additional structural features of the receptor are as described in Freindorf et al. (96).]
On the other hand, the PI3K pathway, which can be activated by T3 via the S1 site of the TH receptor on integrin αvβ3, stimulates cell proliferation and survival and also inhibits apoptosis (57). An apparently inactive analogue of thyroid hormone, rT3, has been shown to induce proliferating cell nuclear antigen (PCNA) expression in U87MG human GBM multiforme cells and MCF-7 human breast cancer cells (165). Alternatively, tetrac and its nanoparticulated analogue have been shown to compete with the binding site of thyroid hormones on integrin αvβ3 and block thyroid hormone-induced cancer growth in vitro and in vivo xenograft (194, 241, 273–275). They are able to induce gene expression including anti-proliferation, anti-inflammation, and pro-apoptosis.
Nevertheless, activation of PI3K induced by T3 can reach through a TRβ-dependent pathway. TRβ can form a complex with the p85 subunit of PI3K and the Src family tyrosine kinase Lyn in cytoplasm in the absence of T3. The association depends on two canonical phosphotyrosine motifs in the second zinc finger of TRβ. When T3 binds to TRβ to cause TRβ to dissociate from the complex and move to the nucleus, in the meantime the product of activated PI3K, phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] increases rapidly (178).
C. Link to Activation of the Integrin
Most integrins exist in resting state before receiving inside-out signaling. Although it has been well-demonstrated that integrin αvβ3 is a thyroid hormone cell surface receptor, the mechanism involved in thyroid hormone-induced activation of integrin αvβ3 is still not understood. The hypoxic microenvironment around tumor cells leads to activation of the transcription factor HIF-1α (206). HIF-1α activates the transcription of many genes facilitating integrin αvβ3 activation (12, 229). In addition to activation under hypoxic conditions, HIF-1α can also be stabilized under a number of normoxic conditions (53, 86) that involve activation of PI3K-Akt-mTOR signaling, Ras and Src. Another example of mTOR-requiring integrin internalization is that involving α5β1 (213). All of them can be upregulated in certain cancers. Additionally, HIF-1α modulates the level of integrin αvβ3 on the cell surface (54) without affecting other integrins such as integrin β1 and integrin β5 (129). Each mechanism may be able to send inside-out messages to activate integrin αvβ3 for thyroid hormone-induced outside-in activation of integrin.
D. Association of Activation of the Integrin and Thyroid Hormone Receptor to Radiosensitivity of Tumor Cells
Radiotherapy has been used for certain types of cancers, but radioresistance is a substantial barrier to success in cancer management. A number of molecular mechanisms support radioresistance. Glioblastomas recur predictably after radiation treatment. This in part is due to radiation-induced signaling events in endothelial cells that support angiogenesis (173). The extracellular domains of certain integrins may alter their conformation in response to radiation exposure, and such changes are associated with development of radioresistance (205). Several extracellular integrins have been shown to be involved in radioresistance. Integrin α6 cleavage increases resistance of human prostate cancer to ionizing radiation (205). Blocking integrin cleavage in vivo may be efficacious for increasing the radiation-induced responsiveness of slow-growing, pro-metastatic human prostate cancer. Integrin αv has been shown to induce multicellular radioresistance in human nasopharyngeal carcinoma (202). Integrin β1 signaling is essential for human head and neck cancer resistance to radiotherapy (88). In addition, extracellular domain of integrin αvβ3 may modulate the state of radiosensitivity of tumor cells.
Cellular signal transduction pathways are involved in integrin-dependent radiation resistance. Integrin αv-induced radiation resistance is via activating SAPK/JNK pathway (202). FAK/cortactin signaling is essential for β1 integrin-dependent radiation resistance in human head and neck cancer resistance to radiotherapy (88). Matrix metalloproteinase (MMP)-2 regulates SDF-1/CXCR4 signaling-mediated angiogenesis in endothelial cells (173), suggesting the anti-angiogenic efficacy of combining downregulated MMP-2 and radiation when treating patients with GBM in the future (173).
Evidence indicates that radiotherapy may affect physiological thyroid hormone. One study showed that 19 patients (26%) had hypothyroidism, although a majority of patients (61%) had a normal thyroid function (6). Various signal transduction molecules may induce or support existing radioresistance in tumor cells. The activities of some of these molecules are regulated by T4 via its receptor on integrin αvβ3 and are thus subject to downregulation by tetrac, which has been shown to oppose radioresistance in cancer cells (143).
E. Links to Signal Transduction Systems
Thyroid hormones bind to integrin αvβ3 to activate ERK1/2 signal transduction pathway. In addition, T3 activates PI3K and downstream AKT. However, thyroxine can activate PI3K activation in oral cancer SCC25 and OEC-M1 cells (37). It is not clear if thyroxine-induced PI3K is a phenomenon of cell specificity. Interestingly, although tetrac and nano-diamino-tetrac (NDAT, also designated Nanotetrac) bind to integrin αvβ3 receptor (40), they inhibit ERK1/2 and PI3K activation with the exception of NDAT activating ERK1/2 in colorectal cancer HT29 cells (40, 151). Recently, studies also indicate that thyroid hormones (T3 and T4) induce proliferation in multiple myeloma cell lines via the αvβ3 integrin-ERK1/2 pathway (48). A thyroid hormone analog, 3,5-diiodothyropropionic acid (DITPA), with inotropic but not chronotropic properties at nanomolar concentrations, exhibits potent proangiogenic activity that is inhibited by NDAT, ERK1/2 inhibitor, PD 98059, and a specific small molecule antagonist of integrin αvβ3, XT199 (192).
F. Regulation in Cancer Cells of Expression of Specific Genes by the Cell Surface Hormone Receptor in Response to Thyroid Hormone
TABLE 1 lists a panel of tumor-relevant genes the transcription of which is differentially regulated by thyroid hormone and initiated at integrin αvβ3. The gene products of VEGF and bFGF, HIF-1α, MMP-9, and nitric oxide synthase-2 (NOS-2) have actions linked to angiogenesis. Apoptosis-linked genes whose expression is modulated by T4 include apoptotic protease activating factor 1 (APAF1), caspase 3 (CASP3), and bcl-2 binding component 3 [BBC3 or p53 upregulate modulator of apoptosis (PUMA)]. As TABLE 1 indicates, the action of T4 on each of these genes has a vector that supports tumor cell survival.
| Gene | Up- or Downregulation of Transcription | Reference Nos. |
|---|---|---|
| Pro-angiogenesis genes | ||
| FGF2 | ↑ | 57 |
| HIF-1α | ↑ | 162 |
| iNOS | ↑ | 36 |
| MMP-9 | ↑ | 50 |
| VEGF | ↑ | 33 |
| Pro-apoptosis genes | ||
| APAF-1 | ↓ | 48 |
| CASP3 | ↓ | 48 |
| NOXA | ↓ | 48 |
| PUMA | ↓ | 48 |
| Anti-apoptosis genes | ||
| COX-2 | ↑ | 162 |
| SREBP-1 | ↑ | 103 |
| XIAP | ↑ | 157 |
It should also be pointed out that tetrac or chemically modified tetrac (Nanotetrac, NDAT) affects the expression of epidermal growth factor receptor (EGFR), thrombospondin 1 (TSP1), X-linked inhibitor of apoptosis (XIAP), and certain microRNAs that are important to cell division of tumor cells and tumor cell survival pathways (61). Mutations of the EGFR gene underlie uncontrolled growth of a variety of types of cancer, and action of tetrac derivatives on transcription of this gene would appear to be a particularly important function of this compound.
Such observations suggest that T4, the parent compound of tetrac, may also affect transcription of certain of these genes. Because tetrac has actions in a variety of models that oppose the effects of T4, we would expect any effects of T4 on tetrac-responsive genes to be opposites of those of tetrac and thus in support of cancer cell survival.
G. Intracellular Consequences of Signals Generated at αvβ3
Cell proliferation is always associated with spreading and with phosphorylation of the FAK paxillin and ERK1/2. However, cell attachment in the absence of spreading or proliferation is not associated with phosphorylation of any of these proteins. Integrin αvβ3 extremely expresses in cancer cells and proliferative endothelial cells. Integrin αvβ3 interacts with RGD-containing matrix proteins, vitronectin, fibrinogen/fibrin, and fibronectin, through its extracellular domains. It also interacts with intracellular enzymes, adapters, and cytoskeletal proteins through its cytoplasmic tails (93, 208). Different integrin receptors for a single ligand can produce markedly different effects on cell proliferation, and both the extracellular and cytoplasmic domains of integrin β subunits contribute to these differences (278). Kindlins, a class of intracellular adapter proteins (208), modulate various aspects of bidirectional signaling mediated by β1, β2, and β3 integrins through direct interactions with integrin β cytoplasmic tails and with intracellular binding partners such as actin, integrin-linked kinase, migfilin, c-Src, and phosphoinositides (176, 212, 220). β3ΔRGT knock-in mice expressing β3 that lack these three COOH-terminal residues exhibit reduced pathological tumor-related angiogenesis when compared with wild type, suggesting that αvβ3-kindlin-2 interaction plays a positive role in angiogenesis (150). Cellular l-arginine uptake and nitric oxide (NO) production are dependent on the arginine transporter. Thyroid hormone induces l-arginine transporters mediated by activation of integrin αvβ3 receptor and subsequent PI3K, ERK1/2, and intracellular Ca2+ signaling pathways. Sequentially, it stimulates l-arginine metabolism and NO production (259). Thyroid hormone as T3 activates FAK and its translocation at cellular sites where there is assembly of focal adhesion complex formation that supports actin remodeling and translocation. Relevant to this process is intracellular signaling initiated at integrin αvβ3 that results in action of Src, PI3K, and FAK pathways (95). The nonthyroidal illness syndrome results from serious systemic nonendocrine diseases such as septicemia and is characterized by lowered circulating levels of thyroid hormone, particularly T3 (90, 112). In the murine model of meningococcal infection, the administration of T4 was shown to promote bacterial clearance and improve survival (36). In vitro studies have shown increased NO-dependent macrophage uptake of meningococci in response to T4 (36).
Sertoli cell (SC) protein synthesis and secretory activity are critical to spermatogenesis, and amino acid uptake by SCs is stimulated by thyroid hormone via αvβ3 (284). This process appears to be independent of the nuclear receptors for thyroid hormone. In the liver, a panel of sterol regulatory element-binding proteins (SREBPs), transcription factors relevant to lipogenesis, is stimulated by thyroid hormone as T3, acting on integrin αvβ3 (103).
IV. αVβ3 THYROID HORMONE ANALOGUE RECEPTOR AND CANCER CELL FUNCTION
A. Cancer Cell Proliferation and Regulation of the Cell Cycle
The thyroid hormone analogue receptor on plasma membrane integrin αvβ3 is essential to survival functions of cancer cells (61, 65, 70, 102, 157, 190, 274). Transcription of eight cyclin genes and at least one cyclin-dependent kinase (CDKNK2) gene are regulated by the thyroid hormone receptor (70, 102, 274). The anticancer thyroid hormone analogue tetrac and chemically modified tetrac downregulate expression of cyclin genes. Cancer cell anti-apoptosis (153) and DNA repair (233) are also controlled by thyroid hormone analogues via αvβ and are essential to sustained cell proliferation; they are discussed elsewhere in this review. Whether measured by abundance of PCNA or cell count, the cell proliferation/anti-proliferation response initiated at the integrin is apparent within 24 h after cell exposure to thyroid hormone analogues (241, 273, 275). Specific genes whose cell cycle-related expression is modulated by thyroid hormone analogues that initiate their actions at integrin αvβ3 are listed in TABLE 2.
| Function/Gene | Up- or Downregulation |
|---|---|
| Cell cycle | |
| Cyclins | ↓ |
| CDKN2C | ↑Cyclin-dependent kinase inhibitor |
| Pro-apoptosis | |
| CASP2 | ↑ |
| CAP8AP2 | ↑ |
| DFFA | ↑DNA fragmentation factor subunit α |
| BCL2L14 | ↑ |
| Anti-apoptosis | |
| XIAP | ↓X-linked inhibitor of apoptosis protein |
| Wnt-catenin pathway | |
| CTNNA1 | ↓ |
| CTNNA2 | ↓ |
| CBY1 | ↑Nuclear inhibitor of catenin |
| Anti-angiogenesis | |
| TSP1 | ↑ |
| Vascular growth factors | |
| VEGFA | ↓ |
| bFGF | ↓ |
| Growth factor receptors | |
| EGFR | ↓ |
The foregoing discussion relates to cancer cells, but a small number of nonmalignant cell functions (65) are mediated by the thyroid hormone receptor on αvβ3 and are discussed in other sections of the current review. These functions include angiogenesis and endothelial response to thyroid hormone analogues (76), certain phagocyte functions (36), and activation of platelets (195).
B. Cancer Cell Metabolism and Regulation of Mitochondrial Function
In normal, nonmalignant cells, metabolism is largely regulated in mitochondria by T3 (38, 65). In cancer cells that overexpress and activate integrin αvβ3, a second mechanism appears to be implicated in control of metabolism. Via the thyroid hormone analogue receptor on the integrin, a chemically modified tetrac named P-bi-TAT (214) downregulates expression of a panel of genes important to cancer cell respiration. These include ATP synthase and NADH dehydrogenase (NDUF) genes (64). The synthase genes, such as ATPS5A and ATP51, code for proteins involved in electron transport and oxidative phosphorylation. Such actions broaden the anticancer activity of the tetrac molecule, but also suggest that T4, the endogenous source of tetrac (65), may stimulate respiration in tumor cells by increasing the abundance of families of mitochondrial proteins. This possibility has not been examined. Whether T4 may in cancer cells also stimulate the activity of these respiration-linked enzymes is also unknown.
C. Chemoresistance of Cancer Cells
The molecular mechanisms that underlie expression of chemoresistance in tumor cells are many (4, 287). They include transporter function by which chemotherapeutic agents may be exported from cells, anti-apoptosis systems, DNA repair, and signal transducing oncogenes (e.g., PI3K/Akt and ERK), among other mechanisms. As noted elsewhere in the current review, T4 can induce anti-apoptosis via its receptor on integrin αvβ3, and among the mechanisms are inhibition of the specific phosphorylation of p53 (65, 157). T4 has a number of actions on signal transduction pathways (65), and it also stimulates DNA repair mechanisms (61).
P-glycoprotein (P-gp; multidrug resistance pump 1, MDR1; ABCB1) is a plasma membrane efflux pump that expels chemotherapeutic agents such as doxorubicin and etoposide from tumor cells (66). Thyroid hormone is capable of enhancing pump activity and of inducing expression of the gene (MDR1) for the pump (199). Whether this is mediated by αvβ3 is not yet clear. The T4 antagonist at the integrin, tetrac, increases cancer cell retention of doxorubicin and etoposide (66), consistent with a primary integrin-based action on P-gp. But other actions of tetrac may reduce P-gp function, e.g., decreasing intracellular pH via αvβ3-mediated reduction in activity of the plasma membrane Na+/H+ exchanger (66). The rationale for considering more than a single direct action of tetrac-αvβ3 on P-gp activity is that cisplatin retention is also increased in cancer cells exposed to tetrac or chemically modified tetrac, and cisplatin transport is not a function of P-gp.
The action of thyroid hormone on the Na+/H+ exchanger and extracellular local pH around cancer cells may be complemented by the capacity of the hormone to stimulate plasma membrane Na+-K+-ATPase activity (140, 163). Such coupling importantly will maintain normal intracellular Na+ levels. It is not known whether thyroid hormone activates Na+-K+-ATPase via integrin αvβ3 (163), but the hormone can activate the sodium pump via signal transducing kinases. The latter can be turned on via the integrin or by another and novel nongenomic mechanism involving a nuclear TR (178).
D. Contributions of the αvβ3 Thyroid Hormone Receptor to Radioresistance of Cancer Cells
Radioresistance remains an important barrier to successful treatment of cancers, and the discovery of the thyroid hormone analogue receptor on integrin αvβ3 (19) has linked thyroid hormone to maintenance of certain components of radioresistance (143). Tetrac is capable of restoring radiosensitivity to tumor cells (110, 114, 141). There are a number of molecular mechanisms by which tetrac, derived from T4, may accomplish this change. For example, rapid cellular self-repair of radiation-induced double-strand DNA breaks is essential to tumor cell resistance to radiation, and tetrac via the integrin receptor interferes with DNA repair (61). This effect of tetrac implies that T4 may act at αvβ3 to support such DNA repair, but such an effect has not been specifically examined. MicroRNA-21 (miRNA-21) is associated with radioresistance (143), and its abundance is downregulated by tetrac (61). Epithelial-to-mesenchymal transition (EMT) of cancer cells may also be linked to development of radioresistance, and T4 acts at its integrin receptor to promote EMT (266). Several signal transduction pathways important to successful radioresistance in tumor cells are also disordered by tetrac at αvβ3 (143). Again, these actions of tetrac raise the possibility that T4 enhances radioresistance in cancer cells.
Exposure of cancer cells in vitro to radiation has induced rapid activation of integrin αvβ3, that is, physical assumption of the “open” configuration of the protein (142). As a result, there are more physical and charge interactions among the integrins. This response to radiation is blocked by chemically modified tetrac (142), and the basal configuration of αvβ3 in the absence of radiation is unaffected by tetrac. Given that tetrac in several forms restores radiosensitivity in cancer cells, the physical response of αvβ3 to irradiation is probably related to the state of radioresistance/radiosensitivity. The integrins are factors helping to shrink by protein-protein interactions the intercellular space and the access of oxygen to cells. The activated integrins may promote hypoxia, which is associated with radioresistance (34, 108, 142).
E. Cancer Metastasis and Integrin αvβ3
Molecular mechanisms involved in the cancer metastatic process have recently been reviewed (190). TABLE 3 identifies a panel of driver genes important to metastasis of a variety of cancers whose transcription is blocked by a chemically modified form of tetrac, P-bi-TAT. The latter consists of two tetrac molecules covalently linked to a polyethylene glycol (PEG) molecule (64, 214). P-bi-TAT acts exclusively at the thyroid hormone receptor on cancer cell surface integrin αvβ3.
| Gene | Metastasis of | Reference Nos. |
|---|---|---|
| AKT1 | Breast cancer; colorectal cancer; osteosarcoma; esophageal squamous cell carcinoma; tongue squamous cell carcinoma | 87, 127, 147, 177, 209, 222, 265, 289 |
| AKT2 | Breast cancer; colorectal cancer; multiple cancer types | 1, 118, 218, 222 |
| ERBB2 | Prostate cancer; breast cancer; gastric cancer | 17, 94, 258, 270 |
| HRAS | Breast cancer | 87 |
| IDH2 | Intrahepatic cholangiocarcinoma (biliary cancer); osteosarcoma (loss of tumor suppressor function); hepatocellular carcinoma; low-grade diffuse glioma | 97, 221, 253, 276 |
| KIT | Breast cancer; prostate cancer; colorectal cancer; melanoma; gastrointestinal stromal tumors | 125, 130, 134, 175, 224, 236, 249, 267, 285 |
| MAP2K7 (MKK7) | Lung cancer; colon cancer; pancreatic cancer | 211, 223, 288 |
Angiogenesis at the sites of nesting of circulating cancer cells is essential to survival of metastases. A substantial number of actions of thyroid hormone analogues at the integrin regulate new blood vessel formation (76, 191). T4 has been shown to be pro-angiogenic in model systems such as the chick chorioallantoic membrane (19), and tumor xenograft angiogenesis has been shown to be inhibited by tetrac-based products (76, 191), as discussed elsewhere in this review.
Also contributing to metastasis and subject to regulation by thyroid hormone analogues at αvβ3 are EGFR (61, 190), miR-21 (61), and certain MMPs (30, 251). The transcription of several specific MMP genes is subject to regulation at αvβ3 by thyroid hormone analogues (50, 61).
Local platelet release of ATP in response to T4 may also contribute to component mechanisms of cancer cell metastasis, as shown in FIGURE 5. Such mechanisms include tumor cell EMT and potentiated actions of MMP-9 and of β-catenin (74). The topic of T4-induced, αvβ3-mediated ATP release by platelets is discussed in section XII.
FIGURE 5.Platelet degranulation (ATP release) induced by l-thyroxine (T4) at the site of tumor cell-platelet interaction. Degranulation is stimulated by the binding of T4 to the thyroid hormone analogue receptor site on platelet membrane integrin αvβ3 (195). Extracellular ATP and cancer cell ATP uptake results in activation of a set of discrete pathways linked to enhanced tumor cell migration and metastasis. ATP-stimulated factors related to invasiveness include protease activated receptor 2 (PAR-2), S100 calcium-binding protein A4 (S100A4), matrix metalloproteinase-9 (MMP-9), and β-catenin. T4 may cause local release of ATP from platelets (sect. XII), and platelet-tumor cell interactions are a component of nascent sites of metastasis. Activation of cellular epithelial-to-mesenchymal transition (EMT) also results from increased extracellular ATP around cancer cells. It is not clear whether the platelet αvβ3-tumor cell plasma membrane αvβ3 interaction is fibrinogen-stimulated (136), as proposed in this figure, and directly activated by T4. Thyroid hormone may increase circulating levels of fibrinogen (73) and activates various functions of integrin αvβ3 (65), but the tumor cell-platelet interaction via αvβ3 has not yet been studied. [From Davis et al. (74), with permission from Springer Nature.]
F. Specific Cancers Shown to Be Subject to Control by Thyroid Hormone via αvβ3
Xenograft studies and/or in vitro cell culture studies have shown a substantial number of cancers to be regulated by thyroid hormone analogues, such as T4 (stimulation of proliferation, anti-apoptosis, pro-angiogenesis) or tetrac derivatives (inhibition of proliferation, pro-apoptosis, anti-angiogenesis). These malignancies include pancreatic cancer (78), breast cancer (20), non-small-cell lung carcinoma (194), follicular thyroid cancer (272), GBM (241), medullary carcinoma of the thyroid (274), renal cell carcinoma (273), melanoma (11, 89), ovarian cancer (232, 266), lymphoma (9, 84), and myeloma (46, 50).
G. Clinical Evidence that Specific Thyroid Hormone Analogues Modulate Clinical Cancer Growth
Coincidental, spontaneous hypothyroidism may offer improved long-term tumor behavior in breast carcinoma (55), as may hypothyroidism as an unintended consequence of medical therapy in head-and-neck carcinoma (198) and renal cell carcinoma, where the latter has been treated with tyrosine kinase inhibition (27, 227). Exogenous thyroid hormone promoted pancreatic cancer progression in patients with hypothyroidism (225).
Intended medical induction of primary hypothyroidism in patients with advanced cancers of various types may improve outcomes (111, 113). Hypothyroxinemia appears to be more important than reduction of both T3 and T4 (111).
V. αvβ3 THYROID HORMONE RECEPTOR AND INTRACELLULAR PROTEIN TRAFFICKING, e.g., NUCLEAR UPTAKE OF CYTOPLASMIC ERK1/2, THYROID HORMONE NUCLEAR RECEPTOR (TRβ), AND ERα
A large number of proteins of varying function that are found transiently or reside regularly in cytoplasm are subject to regulation by thyroid hormone, acting at the receptor on plasma membrane integrin αvβ3. “Regulation” here includes trafficking of proteins among cellular compartments and alteration of certain activities of these proteins. TABLE 4 lists some of these proteins found regularly in cytoplasm that are subject to control by actions of iodothyronines at the cell surface.
| Protein | Trafficking | Function(s) | Reference Nos. |
|---|---|---|---|
| TRα | Nucleus | Transcription; activation of NOS | 32 |
| TRβ1 | Nucleus | Transcription | 60 |
| ERKs | Nucleus | Signal transduction | 162 |
| PI3K | Nucleus | Signal transduction | 162 |
| ERα | Nucleus | Transcription | 119 |
| CTBP | Cytoplasmic residence | Nuclear TH uptake | 283 |
| Integrin αv monomer | Plasma membrane-cytoplasm-nucleus | Transcription | 160 |
Signal transducing kinases such as the ERKs and PI3K/AKT that are subject to activation in cytoplasm by T4 action at αvβ3 may bind to TRs, and the resulting complex has access to the nuclear compartment. Cytoplasmic TRα1 is bound by the p85 subunit of PI3K and fosters NOS activation in ischemic tissue (115). Cytoplasmic TRβ1 complexed with activated PI3K and transported into the nucleus has been shown to stimulate transcription of a number of genes (182, 183), and it is now known that this trafficking can be enhanced from the thyroid hormone receptor on αvβ3, leading, for example, to HIF-1α gene expression (162).
Studied in human ovarian cancer cells, activation (phosphorylation) of ERα and its translocation to the nucleus from cytoplasm was induced by T4, as well as by estradiol (E2) (119). The T4 effect requires ERK1/2 activation and is initiated at integrin αvβ3. Cancer cell proliferation results from the action of T4 and was subject to inhibition by an ERα antagonist, ICI 182,780 (fulvestrant), and fulvestrant blocked actions of T4 on MAPK activation and phosphorylation of ERα. This hormonal effect was also blocked by fulvestrant. The overlapping of actions of thyroid hormone and estrogen in tumor cells may have particular clinical significance in the postmenopausal woman with ERα-expressing cancer, where T4 may assume the role of estradiol in terms of tumor support.
Another remarkable consequence of the action of T4 on ovarian cancer cells at αvβ3 is that it results in the driving of integrin αv monomer from the cell surface to the nucleus and to liganding of the monomer to the promoter region of the ERα gene (119). This is a MAPK-requiring process. Transcription of this gene is enhanced by the binding of T4-directed integrin monomer (160). These studies were extended to ERα-expressing lung cancer cells and, again, T4 via the αv monomer caused expression of the ERα gene. In both ovarian and non-small-cell lung cancer cells, the action of T4 on αv trafficking to the cell nucleus also resulted in co-activator function at the HIF-1α, COX-2, and TRβ1 genes (160), whose expression is important to tumorigenesis and angiogenesis. Monomeric αv in the nuclear compartment may interact with other transcriptional co-regulator proteins.
PI3K may also be directed from cytoplasm to the nucleus by thyroid hormone (162). In the nucleus or in the course of cytoplasm-to-nucleus trafficking, PI3K may phosphorylate TRα1, and this may be associated with specific gene transcription, e.g., HIF-1α. These effects appear to be T3-specific at plasma membrane αvβ3. As noted elsewhere in this review, the iodothyronine receptor on the integrin has a T3-specific site (S1) and a site that binds both T4 and T3 (S2) and activates ERK1/2 (162). T4 is the primary ligand at S2, taking into account the concentration of T4 that is active at this site.
μ-Crystallin (ketimine reductase) and pyruvate kinase M1 are additional cytoplasmic proteins that bind thyroid hormone and are discussed in section I. It is not clear that these proteins are subject to trafficking by thyroid hormone, but the binding of the hormone may change the biochemical activities of these enzymes.
CTBPs are also mentioned in section I. In the cases where they have not been identified as specific proteins, e.g., enzymes, such proteins may serve to regulate the nuclear uptake of T3 or the access of cytoplasmic T4 or T3 to plasma membrane or sarcoplasmic reticulum proteins with specific functions (137, 163, 264). It is not yet clear whether any of these proteins are directed into the nuclear compartment by thyroid hormone.
VI. INTEGRIN αvβ3 THYROID HORMONE RECEPTOR AND PHOSPHORYLATION/ACTIVATION OF NUCLEAR HORMONE RECEPTORS, e.g., TRs, ERα
The description of the activation of signal transducing ERK1/2 by physiological concentrations of T4 (154) led to reports of the specific phosphorylation/activation of nuclear TR (75) and of ERα (250). These actions indicated the existence of overlapping nongenomic actions of T4 at MAPK and downstream modulation by MAPK of the activity of TR essential to genomic actions involving T3 (38, 65). With the description of the cell surface receptor for T4 and other thyroid hormone analogues on integrin αvβ3 (19) came the subsequent understanding that actions of T4 on MAPK were initiated at the integrin and led to association of MAPK with TR and ERα and nuclear uptake of the kinase-receptor complexes (38, 65, 71).
Such actions of T4 on the state of nuclear thyroid hormone and estrogen receptors were appreciated to be of particular importance to certain types of cancer cells (119, 180). In human ovarian cancer cells, for example, the induction by T4 of cell proliferation was shown to be largely dependent on the activation of ER, since the specific ERα antagonist ICI 182,780 (fulvestrant) blocked the effect of T4 on ERK1/2-requiring cell proliferation (119). The T4 effect was documented to require intact αvβ3. Another remarkable feature of these observations is that T4 caused the cellular internalization and nuclear uptake of monomeric αv; the latter co-localized in the nucleus with ERα. This raised the possibility that αv may function as a co-activator protein in thyroid hormone-treated cells. In human lung carcinoma cells that express ERα, it was similarly shown to be important to the action of T4 on proliferation (180). Interestingly, TRs in such cells were not primarily responsible downstream for the action of T4 initiated at the integrin.
Phosphorylation of nuclear receptor plays important roles in receptor stability and their transcriptional ability (254, 255, 269). Thyroid hormone binds to cell surface receptor integrin αvβ3 to activate ERK1/2 phosphorylation, which promotes ERK1/2-dependent serine phosphorylation of TRβ1. The consequences are dissociation of TR and SMRT. In addition, activation of cAMP-dependent protein kinase (PKA) plays a role in TR phosphorylation (144, 260). Studies by Katz et al. (132) summarized that serine phosphorylation of the receptor isoform decreased its ability to heterodimerize with retinoid X receptor at a thyroid hormone response element site when phosphorylatable and nonphosphorylatable forms of TRα2 were compared. Selectively serine-phosphorylated TRβ1 is more stabilized against protease degradation (254, 255). Transcriptional activity of TRβ1 is significantly increased after serine phosphorylation (144, 254, 255). Although serine-phosphorylated TRα1 has been shown to decrease TR monomer binding to DNA (260), research of Jones et al. (128) indicates that a reduction in transcriptional activity of both TRα1 and TRβ1 is induced by T3 using a serine/threonine kinase inhibitor, H7. However, the results may be highly cell-specific (144).
T4 stimulates expression of ERα via integrin αvβ3 (107, 119, 160). In addition, T3 can induce ERα expression without affecting ERβ1 or ERβ2 (203). Studies of confocal microscopy and biochemical data indicate that integrin αvβ3 and ERα formed complexes apparently linked to ovarian cancer proliferation. Interrupting complex formation inhibits proliferation partially (203). Thyroid hormone binds to cell surface receptor integrin αvβ3 to activate ERK1/2 phosphorylation and further recruits ERα to form integrin αvβ3-ERα complex. Sequentially, thyroid hormone induces cell proliferation in ovarian cancer cells through ERK1/2-dependent serine phosphorylation of ERα, S167, which mimics the effect of estrogen in ERα-positive breast cancer (250) and non-small-cell lung cancer cells (180). The ER antagonist ICI 182,780 blocks the thyroid hormone-induced effect, suggesting that crosstalk between thyroid hormone and estrogen signaling pathways occurs. In addition to the contribution from integrin αvβ3, thyroid hormone-induced ERα phosphorylation also plays a crucial role in thyroid hormone-induced proliferation in ovarian cancer cells (119). In summary, cooperation of ERα and αvβ3 enhances the proliferative effect of thyroid hormone in cancer cells.
Nuclear receptors are present in different types of cancer cells. Crosstalk among different receptors may contribute to the hormone sensitivity differences observed in different cancer cells. For example, OVCAR-3 cells do not have detectable ERα but do have integrin αvβ3, which is more sensitive to integrin αvβ3 blockage using RGD peptide. SKOV-3 cells express both αvβ3 and a high level of ERα and are more sensitive to ICI 182,780 (119). Although there is no evidence if the thyroid hormone-integrin αvβ3 pathway plays a role in androgen receptor phosphorylation, we have shown that DHT binds to integrin αvβ3 to stimulate ER-negative MDA-MB breast cancer cell proliferation (42, 161). These observations suggest that crosstalk between integrin αvβ3 may be involved in androgen receptor phosphorylation.
VII. αvβ3 THYROID HORMONE RECEPTOR AND ANGIOGENESIS
The mechanisms by which thyroid hormone analogues act at integrin αvβ3 to regulate angiogenesis have been extensively reviewed (76, 191). The original description of the hormone receptor on αvβ3 was based on an angiogenesis assay system, the chick chorioallantoic membrane (CAM) model (19) (FIGURE 6).
FIGURE 6.Pro-angiogenic activities of l-thyroxine (T4). A: T4 coupled to agarose (T4-agarose), which does not gain access to the cell nucleus, and vascular endothelial growth factor (VEGF) as determined in the chick chorioallantoic membrane angiogenesis assay. B: factor concentrations are listed. Vessel branch points were counted and differences from control specimens statistically analyzed at 24 h. PBS, phosphate-buffered saline. [From Davis et al. (76).]
A basic concept is that at αvβ3, thyroid hormone analogues T4 and T3 are potent pro-angiogenic agents, whereas tetrac and chemically modified tetrac (such as Nanotetrac) are anti-angiogenic (76). TABLE 5 summarizes some of the pro-angiogenic pathways or factors by which T4 or T3 stimulate angiogenesis, and TABLE 6 lists anti-angiogenic mechanisms of tetrac and Nanotetrac (NDAT). The tables are complimentary and indicate that actions of tetrac molecules are not simply an antagonism of the properties of T4 and T3. It is clear that angiogenesis actions initiated by thyroid hormone analogues at αvβ3 involve multiple steps in blood vessel formation, and the actions on vessel growth factors may be focused on gene expression and on cellular release of growth factors, as well as on crosstalk between cell surface αvβ3 (80% or more of the mass of which is extracellular) and adjacent receptors for vascular growth factors. As examples, VEGF and bFGF gene transcription in endothelial cells may be modulated, the rate of release of these growth factors into the extracellular space may be changed, and the function of nearby VEGFR and bFGFR (receptors for these growth factors) may be altered (TABLES 5 and 6). This is a comprehensive set of control mechanisms by which to modify new blood vessel formation. The biology of platelet-derived growth factor (PDGF) and of the EGFR also involves blood vessels, and both factors are subject to regulation by thyroid hormone analogues. In contrast, clinical agents currently directed at angiogenesis usually target single vascular growth factor proteins.
| Angiogenesis-Relevant Target | Action | Reference Nos. |
|---|---|---|
| bFGF transcription | ↑ | 2, 57, 286 |
| bFGFR transcription | ↑ | 2 |
| HIF-1α transcription | ↑ | 162, 169 |
| VEGFA transcription | ↑ | 286 |
| VEGF transcription | ↑ | 169 |
| PDGF transcription | ↑ | 35 |
| PDGFR transcription | ↑ | 35 |
| Cellular bFGF abundance | ↑ | 57 |
| Cellular PDGFR abundance | ↑ | 35 |
| Cellular release of bFGF | ↑ | 57 |
| Cellular release of VEGF | ↑ | 81 |
| Endothelial cell mobility in response to cue | ↑ | 191 |
| Proliferation of brain endothelial cells | ↑ | 286 |
| Angiogenesis-Relevant Target | Action | Reference Nos. |
|---|---|---|
| bFGF transcription | ↓ | 57 |
| VEGFA transcription | ↓ | 60, 274 |
| EGFR transcription | ↓ | 102 |
| TSP1 (THBS1) transcription | ↑ | 102, 274 |
| IL-6 transcription | ↓ | 62 |
| miR-21 transcription | ↓ | 193 |
| miR-15A transcription | ↑ | 193 |
| Cellular bFGF abundance | ↓ | 57 |
| Cellular Ang-2 abundance | ↓ | 188 |
| Cellular MMP-9 abundance | ↓ | 50 |
| Integrin αvβ3-bFGFR crosstalk | ↓ | 188 |
| Integrin αvβ3-VEGFR crosstalk | ↓ | 188 |
| Integrin αvβ3-PDGFR crosstalk | ↓ | S. A. Mousa, unpublished observations |
| Cellular release of bFGF | ↓ | 57 |
| Endothelial cell motility in response to cue | ↓ | 191 |
| Pro-angiogenic activity of thyroid hormone | ↓ | 191 |
Endothelial cell levels of certain microRNAs relevant to angiogenesis are also subject to control by tetrac and Nanotetrac (TABLE 6). The observation that the EGFR gene is subjected to control by thyroid hormone analogues (TABLE 6) (102) is relevant to angiogenesis and to tumor cell biology. TSP1 is an anti-angiogenesis factor that is rarely, if ever, expressed by tumor cells, but TSP1 transcription is subject to stimulation by the tetrac analogues of thyroid hormone (TABLE 6) (102).
Thyroid hormone analogues have substantial actions via αvβ3 on the transcription of cytokine and chemokine genes (63, 191). It can be pointed out, for example, that chemokine ligands CXCL2 and CXCL3 are pro-angiogenic, and expression of their respective genes is thyroid hormone analogue controlled via αvβ3 (191). Genes for the CX3C chemokine ligands and receptors are also subject to control by thyroid hormone (63, 191) and make important contributions to angiogenesis in terms of structural integrity and size of new vessels (191). MMPs are other factors that contribute to blood vessel integrity, particularly during tissue remodeling; transcription of the MMP-9 gene is stimulated by thyroid hormone at its receptor on integrin αvβ3 (50).
Another factor important to angiogenesis that is thyroid hormone-managed from αvβ3 is endothelial cell migration in response to blood vessel-relevant, extracellular protein cues, such as vitronectin (191). T4 and T3 enhance cell movement responses to vitronectin, and tetrac blocks the effect of T4 and T3.
FIGURE 7 depicts the complex interactions that are mediated by αvβ3 of thyroid hormone analogues and components of the process of angiogenesis.
FIGURE 7.Schematic diagram of mechanisms of integrin-dependent, nongenomic actions of l-thyroxine (T4,), 3,5,3′-triiodo-l-thyronine (T3), and a thyroid hormone antagonist, nano-diamino-tetrac (Nanotetrac), on angiogenesis. T4 and T3 are pro-angiogenic at the integrin of endothelial cells by amplifying vascular growth factor signals [vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF)] at the growth factor receptors that are adjacent to αvβ3. Nanotetrac is anti-angiogenic by multiple mechanisms. The agent 1) inhibits amplification by T4 and T3 of vascular growth factor signals and 2) disrupts specific growth factor interactions with growth factor receptor in the absence of T4 and T3. Nanotetrac also blocks the pro-angiogenic actions of bradykinin, angiotensin II (Ang II), and lipopolysaccharide (LPS) by mechanisms that appear to depend on αvβ3. Local release of angiopoietin-2 (Ang-2) and matrix metalloproteinase-9 (MMP-9) is an anticipatory step in angiogenesis and is also decreased by Nanotetrac, but the mechanism is not yet known. Not shown is the anti-angiogenic effect of Nanotetrac involving modulation of transcription of angiogenesis-relevant genes; these genes are listed in TABLE 6. [From Davis et al. (76).]
We have pointed out elsewhere that suboptimal clinical responses of cancers to therapy that exclusively targets tumor-relevant blood vessel formation may reflect the influences of host thyroid hormone that is multifaceted and profound stimulus to angiogenesis (78, 191). The observations reported in this section reflect actions of thyroid hormone, specifically T4, in physiological concentrations (19). In contrast, the action of host T4 at sites of desirable angiogenesis, such as wound healing (FIGURE 8) and localized infection, is desirable.
FIGURE 8.Effect of l-thyroxine (T4)-agarose versus control (DMEM + 5% fetal bovine serum) on gap closure of wounded monolayers of human dermal fibroblast cells in vitro. T4-agarose-treated cultures closed faster and had greater cell proliferation than controls. Closure of T4-treated cultures occurred at 12 h at 37°C, compared with control that had no significant closure. T4-agarose does cross the plasma membrane and acts exclusively at the integrin thyroid hormone receptor (189). Method used was a modification of Stewart et al. (238) and Mohamed et al. (184). [From Davis et al. (76).]
VIII. INTEGRIN αvβ3 THYROID HORMONE RECEPTOR AND ANTI-APOPTOSIS
A number of descriptions are available of the regulation of apoptosis in cancer cells by thyroid hormone analogues that act at αvβ3 (153, 156, 157, 164, 166, 232). T4 is anti-apoptotic by multiple mechanisms and serves to support the anti-apoptotic defense pathways of tumor cells (157), and tetrac and chemically modified forms of tetrac are pro-apoptotic (61).
The molecular bases of the anti-apoptotic effects of T4 in cancer cells are shown in FIGURE 9. Both the intrinsic and extrinsic pathways of apoptosis—both meeting at the mitochondrion and regulating permeability of the latter—are regulated by T4. Pro-apoptotic targets are downregulated by anti-apoptotic T4 in the pathway, and these include CASP2 and -3, MCL-1, and BAX genes. Anti-apoptotic targets that are upregulated by T4 include XIAP and BCL-xL (FIGURE 9). In contrast, pro-apoptotic Nanotetrac (NDAT) decreases expression of anti-apoptotic XIAP and MCL1 genes. Nanotetrac also enhances the expression of pro-apoptotic genes for TP53, PIG3, BAD, and CASP-2 (61).
FIGURE 9.Schematic overview of extrinsic and intrinsic apoptosis pathways in the cell and points at which thyroid hormone in these pathways is anti-apoptotic. The pathways converge at the mitochondrion and cause its permeabilization, with release of cytochrome c and consequent apoptosis. Genes or proteins circled in red or green identify loci of differential actions of thyroid hormone on these multiple factors in apoptosis that are discussed in the current review. Red identifies downregulation of the factor, and green identifies upregulation. The Fas receptor is an activator of the extrinsic pathway by its interaction with Fas ligand. An activator of the intrinsic pathway is DNA damage resulting from factors such as radiation or chemotherapy. Bcl-2, B cell lymphoma-2; Bcl-xL, Bcl-2-related gene, long form; Bad, Bcl-2/Bcl-xL-associated death domain protein; Bak, Bcl-2 homologues antagonist killer protein; Bax, Bcl-2-associated X protein; IAPs, inhibitors of apoptosis; MCL-1, myeloid leukemia cell-1; XIAP, X-linked inhibitor of apoptosis. [From Lin et al. (157), reprinted under a Creative Commons Attribution 3.0 License.]
Unexplored is the possibility that low-grade expression of αvβ3 on the surface of specialized nonmalignant cells such as neurons and myocardiocytes might permit expression of anti-apoptotic effect of T4 that would be desirable. The current authors think this is unlikely, based on limited in vitro studies of fibroblasts from human and monkey in which tetrac failed to affect the proliferation of the cells (H. Y. Tang, H-Y. Lin, and P. Davis, unpublished observations). This suggested that the hormone receptor on αvβ3 was not functional.
T4 is anti-apoptotic in different types of cancer cell lines examined at physiological concentration. Among hormone-induced anti-apoptotic mechanisms are interference with the Ser-15 phosphorylation (activation) of p53 and with TNF-α/Fas-induced apoptosis. T4 also reduces cellular abundance and activation of proteolytic caspases and of BAX. It induces increased expression of XIAP. Evidence indicates that thyroxine-induced anti-apoptotic effects mainly are initiated on the extracellular domain of integrin αvβ3 receptor (157). Hypoxia plays an important role in cardiovascular diseases (240) and cancer cell proliferation (172, 268). Hypoxia inhibits cardiomyocyte proliferation and induces cardiomyocyte apoptosis, but in cancer cells it induces cancer proliferation and chemoresistance. Hypoxia induces expression of integrin β3 and HIF-1α in cardiomyocytes. Nonetheless, thyroid hormone increases expression of integrin β3 and HIF-1α in cancer cells. In addition, integrin β3 overexpression enhances hypoxia-induced cancer cell proliferation. Knockdown of integrin β3 expression by siRNA inhibits T4-induced anti-apoptotic effects in cancer cells. Interestingly, current clinical studies in ovarian cancer patients show that the positive rate of integrin αvβ6 expression was higher in tissue from cervical cancer patients than in healthy controls (148). Coincidently, the levels of expression of PCNA, Bag-1, and Ki-67 in the cervical cancer group were higher, while the levels of the apoptosis-related proteins, Cyto-C, AIF, caspase-3, and p-Akt were lower. These studies suggest that integrin αvβ6 mediates proliferation and apoptosis of cervical cancer cells (148). Although evidence does not show that heterodimeric integrin αvβ3 plays an anti-apoptotic role in cervical cancer, integrin αv monomer is no doubt anti-apoptotic. On the other hand, expression of integrin β3 prevents apoptosis of HL-1 cardiomyocytes under conditions of oxidative stress (231). Competing with thyroid hormone on the integrin αvβ3 receptor, tetrac and its nanoparticulate analogue have been shown to block thyroid hormone-induced proliferation in various types of cancer cells. They block thyroid hormone-induced anti-apoptotic action, allowing Ser-15 phosphorylation of p53 and apoptosis to proceed. They moderate integrin-dependent effects on gene expression in human cancer cell lines to increase expression of a panel of pro-apoptotic genes and decrease transcription of defensive anti-apoptotic XIAP and MCL1 genes. Thyroxine is an endogenous anti-apoptotic factor via different mechanisms to reduce efficacy of chemotherapy-induced apoptosis in αvβ3-expressing cancer cells.
IX. THYROID HORMONE RECEPTOR ON αvβ3 AND IMMUNE FUNCTION
The actions of thyroid hormone on the immune response have recently been reviewed (126, 262) but have not distinguished between or among underlying molecular mechanisms. In contrast, thyroid hormone-immune system reviews by De Vito and co-workers (79, 80) some years ago emphasized nongenomic mechanisms, as we will do here, limiting attention to αvβ3-dependent actions. Cells involved in immune responses include dendritic (antigen-presenting) cells, lymphocytes and monocytes, granulocytes, and macrophages (126, 262). This roster of cells indicates that inflammatory responses often complement immune system activities. We have noted elsewhere in this review that T4 may activate macrophages (36) as an antibacterial response, and macrophages may be involved in the clean-up of detritus that may not be immune system in origin.
Integrin αvβ3 is expressed on the surface of multiple types of cells involved in the immune response (247), but this phenomenon has not as yet fostered extensive study of thyroid hormone effects on such cells. It is clear that thyroid hormone as T3 can stimulate generation of reactive oxygen species in mononuclear and granulocytic cells that may enhance cell migration (16, 174). As pointed out above, however, T3 is not a principal ligand of the integrin, and it is not clear that αvβ3 is mediating this nongenomic effect of T3 on reactive oxygen species production.
Thyroid hormone analogues modulate the expression of a number of cytokine and chemokine genes that are linked to the immune response (63). We have shown that certain pro-inflammatory chemokine genes, such as CX3CL1 (fractalkine) and CX3CR1, are transcribed in response to thyroid hormone action at αvβ3 (62). The biological activity of interferon-γ (IFN-γ) on the antiviral response (159, 167) and on human leukocyte antigen-DR isotype (HLA-DR) expression (159, 168) is enhanced by T4. These effects were described before the receptor for iodothyronines on integrin αvβ3 was described (19), but these effects on HLA-DR elaboration and on antiviral function were both blocked by tetrac and thus are very likely to be mediated by the hormone receptor on αvβ3. Furthermore, this integrin has been implicated in recognition of specific viruses (101). Enhancement of host antiviral response by thyroid hormone is desirable, but the action on HLA-DR expression may be deleterious to grafted organ survival and may support autoimmune disease. It has been postulated that the αvβ3-dependent actions of thyroid hormone analogues on chemokine elaboration may support certain disease processes, including neurodegenerative disorder (155).
Acting via αvβ3, thyroid hormone analogues also regulate the activity of the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) immune checkpoint (152). Produced and released by tumor cells, PD-L1 interacts with T lymphocyte PD-1 to block the latter’s contribution to host patient anticancer immune response. T4 stimulates PD-L1 production, thereby supporting a cancer cell defense pathway. T4 also enhances tumor cell accumulation of (non-secreted) PD-L1, and cytoplasmic PD-L1 has been shown to be anti-apoptotic in tumor cells (152). Nanotetrac downregulates transcription of PD-L1 by cancer cells (151). It is not known whether transcription of genes relevant to other immune checkpoints, such as CTLA-4, is affected by thyroid hormone analogues.
These isolated findings are of interest pathophysiologically and indicated a need for more extensive studies of the roles of thyroid hormone at αvβ3 on the various populations of cells involved in immune function and in inflammation associated with the immune response. For example, integrin αvβ3 on pulmonary T lymphocytes appears to mediate lung inflammation and fibrosis (171); are these pathological processes subject to modulation by thyroid hormone analogues? The activity of certain autoimmune diseases, such as systemic lupus erythematosus, reflects the efficiency of clearance of necrotic lymphocytes at sites of disease activity (23). Clearance of dead cells in part is a function of the activity state of αvβ3 of phagocytic cells. Is endogenous host T4 a factor in determining the activity state of the integrin in loci of disease activity?
X. αvβ3 THYROID HORMONE RECEPTOR AND SENSORY NEURON Na+ CURRENT
In a zebrafish model using Rohon-Beard (RB) sensory neuron cells, which are present during embryonic development, Yonkers and Ribera (280) showed that there is thyroid hormone regulation via αvβ3 of sensory neuron sodium current (INa). In particular, they found that acute application of T4 rapidly affected INa such that the data support a nongenomic mechanism for this T4 signaling. The authors added either T4 or T3 to the embryos and within 5 min saw T4, but not T3, significantly increase INa amplitudes. Application of tetrac blocked this effect of T4. In further work, the authors studied the signaling mechanisms responsible for this nongenomic T4 activity and found that zebrafish neuronal cells that express both αvβ3 and the sodium channel Nav INa rapidly responded to T4 and increased INa amplitude (279). It was also found that the MAPK (p38) pathway is involved in the mechanism of RB INa response to T4, but there was little involvement of the ERK1/2 pathway.
XI. αvβ3 THYROID HORMONE RECEPTOR AND BACTERIAL PHAGOCYTOSIS
Bacterial phagocytosis and the impact of thyroid hormone on regulating meningococcal infection in mice were studied by Chen et al. (36). They found that thyroid hormone treatment (T3 or T4) increased the bacterial activity of macrophages and was mediated nongenomically at integrin αvβ3. Pathways PI3K and ERK1/2 were involved to enhance NO production mediated by inducible NOS. Tetrac prevented this thyroid hormone-induced action. Of note is that T4-treated mice had reduced numbers of bacteria in blood samples and better survival rates compared with control. The nongenomic actions observed were not rapid but instead required at least 18 h stimulation with T3 or T4.
XII. αvβ3 THYROID HORMONE RECEPTOR AND PLATELET FUNCTION/COAGULATION
Derived from the multinucleate megakaryocyte in bone marrow, the mammalian platelet is enucleate and consists of megakaryocyte cytoplasm and fractions of plasma membrane that include integrin αvβ3. Thus there is no nuclear TR in the platelet. In vitro studies of human platelets in whole blood obtained from healthy donors have shown that physiological concentrations of T4, but not T3, induce platelet aggregation and degranulation (195). The latter is an index of platelet activation and includes ATP release, the measurement that was used to monitor degranulation in thyroid hormone studies (FIGURE 10). T3 was not effective as an aggregating factor, and tetrac blocked the actions of T4 on aggregation and degranulation (195). The action of thyroid hormone on platelets is a clear model of a hormone action that is necessarily nongenomic and is initiated at αvβ3. The peak actions on aggregation and ATP release are achieved at 2 h after exposure of platelets to T4.
FIGURE 10.Actions in vitro of l-thyroxine (T4) modifications on human platelet aggregation and secretion of ATP by aggregating platelets. The measurements are reported as a function of time after addition of T4 to diluted whole blood in a Chrono-log Electronics whole blood aggregometer. Human platelet aggregation and degranulation are induced in vitro by T4, but not by 3,5,3′-triiodo-l-thyronine or diiodothyropropionic acid (DITPA). Subthreshold aggregation was induced with collagen and then T4 was added at a concentration of 0.01 µM. [From Mousa et al. (195), reprinted under Open Access, copyright owned by authors.]
A summary of studies of function of human platelets from patients with various diseases, including hyperthyroidism and hypothyroidism, has yielded inconsistent results (73, 195). The patients had complex clinical profiles that were likely to have affected circulating levels of cytokines and chemokines that, among other factors, regulate platelet function (73). Larger, more carefully controlled clinical studies are needed to determine how significant the spontaneous changes in endogenous T4 can be in patients. Of particular importance to platelet function may be high blood levels of T4 in thyroid cancer patients receiving exogenous T4 to suppress endogenous thyrotropin.
XIII. NONGENOMIC REGULATION OF THE STATE OF CELLULAR ACTIN
The thyroid hormone-dependent conversion of soluble actin to fibrous actin has been explored extensively by Leonard and co-workers (65, 91, 146, 234). The conversion process described in nervous system cells is enabled by T4 and by rT3, but not by T3, and requires the presence of a truncated TR isoform (TRΔα1) (65). It is not known whether the thyroid hormone receptor on plasma membrane αvβ3 is involved in the regulation of the state of actin, although T4 and rT3 (165) are important ligands of this receptor and there are functional links between the actin cytoskeleton and αvβ3 (14, 100, 239).
The action of thyroid hormone on the cell pool of fibrous actin is a contribution to cell structure and function, notably, the alignment of intracellular trafficking and signaling pathways. The action is also essential to normal cell division. Cell migration in response to a variety of cues in the immune and inflammatory responses also requires a stable cell structure.
XIV. PHARMACOLOGICAL ANTAGONISTS OF THE THYROID HORMONE RECEPTOR ON INTEGRIN αvβ3
A. Thyroid Hormone Analogues (Tetrac, Triac) and RGD Peptides
The biological activity of T4 and T3 at the integrin have been extensively examined in the prior sections of this review and elsewhere (38, 65, 69, 77). The current review and other sources (65, 69, 77) have also explored the role of tetrac as an antagonist of the actions of T4 and T3 at αvβ3. It has been emphasized that activities of T4, the primary ligand of thyroid hormone receptor on integrin αvβ3, can be inhibited by tetrac because in high concentrations it displaces T4 from the site. We have also noted, however, that tetrac in the absence of T4 has a large number of effects that are largely cancer- and angiogenesis-relevant. Thus tetrac can act as an antagonist and protagonist at αvβ3. Both sets of actions are anti-cancer and anti-angiogenic.
Triac (3,5,3′-triiodothyroacetic acid) has been much less well studied. In the cell nucleus, triac, like tetrac, has certain weak thyromimetic activities at TRs (77). Such actions in the nucleus may underlie the limited non-cancer-related preclinical/clinical applications of triac as a weight loss and myogenic agent (149, 179, 226) and for treatment of monocarboxylate transporter 8 (MCT8) deficiency (104). Triac does not appear to affect mitochondria respiration in cancer cells (135). On the other hand, tetrac via αvβ3 decreases mitochondrial respiration in cancer cells (64) by downregulating expression of genes that code for ATP generation.
As noted earlier, rT3 may also act at αvβ3 to stimulate proliferation of human breast carcinoma and glioblastoma cells (77, 165). This thyroid hormone analogue has been seen to be biologically inactive. These tumor cell observations require confirmation, given that endogenous rT3 levels may be elevated in the nonthyroidal illness syndrome that can accompany cancer clinically (112).
RGD peptides bind to a cluster of eight integrins, including αvβ3, where they can modify the actions of thyroid hormone (19). Crystallographic analysis has documented the modest overlap of RGD binding site on αvβ3 and the thyroid hormone receptor (45). The spectrum of genes whose expression is affected by RGD peptides, e.g., cilengitide (201), appears to be far smaller than that modulated by thyroid hormone analogues (64).
B. Anticancer Activity of Thyroid Hormone Analogues such as Chemically Modified Tetrac at αvβ3
Tetrac has anticancer properties expressed at integrin αvβ3 (38, 65), but is internalized by normal, non-cancer cells and by tumor cells and gains access to the nucleus where it expresses modest thyromimetic actions (194, 197, 241, 275). It was desirable, then, if tetrac were to have a role as a cancer chemotherapeutic agent, that it be chemically modified to enhance activity at the integrin and prevent nuclear uptake when it was taken up by cells. An example of such modification was to generate a tetrac nanoparticle by covalently binding the thyroid hormone analogue via its outer ring hydroxyl group to a nanoparticle (20). Bound to a poly(lactic-co-glycolic acid) (PLGA) molecule, tetrac was not taken up by the cell nucleus and interestingly acquired greater anticancer qualities when bound to the integrin. Nanotetrac (NDAT) caused via αvβ3 and signal transduction a set of desirable changes in expression of cancer-relevant genes. These included downregulation of genes for cyclins, for anti-apoptosis, for signal transduction, and for angiogenesis (61, 102). Another chemically modified form of tetrac was generated from covalent bonding of tetrac to PEG (64, 214). This compound differentially affected a greater number of cancer-linked genes (64). The actions of these anti-cancer compounds are reviewed elsewhere (20, 60, 65, 275).
C. Anti-angiogenic Activity of Tetrac-Based Agents Initiated at αvβ3
As noted above, the initial description of the receptor for thyroid hormone analogues on integrin αvβ3 was in an angiogenesis model system, the CAM (19). Tetrac was effectively anti-angiogenic in this system and in other models of angiogenesis (68, 76, 191), as have been chemical modifications of tetrac, such as Nanotetrac. The anti-blood vessel activity of tetrac-based agents is multifaceted (see sect. VII, TABLES 5 and 6).
While the emphasis of initial studies of chemically modified tetrac on angiogenesis has been oncologic, the possibility may be raised that such agents should be tested in models of excessive inflammation or porous neo-angiogenesis in the retina.
D. Pro-apoptotic Action of Thyroid Hormone Analogues Initiated at αvβ3
Cancer cells contain a number of defense pathways that enable resistance to host or chemotherapeutic agent anti-tumor activities. Anti-apoptosis is such a defense with multiple mechanisms. Chemically modified tetrac induces transcription of a panel of pro-apoptotic genes and downregulates certain anti-apoptotic genes (61, 102).
E. Chemically Modified Tetrac Molecules as Drug Delivery Systems Targeting αvβ3
The nanoparticulate PLGA component of Nanotetrac (NDAT) is capable of reversibly encapsulating small drug molecules, such as non-protein cancer chemotherapeutic agents. Examples of such agents are doxorubicin and paclitaxel (243) and cisplatin (242). Enhanced delivery of these agents to tumor tissues has been demonstrated, sparing normal organs of possible toxicity of the drugs. Again, it is the generous expression of αvβ3 by cancer cells, compared with nonmalignant cells, that underlies the result. Because endothelial cells at sites of excessive angiogenesis overexpress αvβ3, it may be possible that anti-inflammatory agents or antibiotics might also be delivered to appropriate tissue sites by nanoparticulate tetrac. These possibilities have not been examined.
XV. OVERVIEW AND AREAS OF INVESTIGATION SUITABLE FOR FURTHER EXPLORATION
Integrin αvβ3 is generously expressed by tumor cells and rapidly dividing endothelial cells (28, 83). Thus it is not surprising that the description of the cell surface receptor for thyroid hormone on this integrin has associated the receptor with cancer cell biology and with angiogenesis (38, 60, 65, 191). The relevance of the receptor and its principal ligand, T4, to cancer biology has been shown to involve control of tumor cell proliferation (47, 58, 59, 166, 233), tumor cell defense pathways [e.g., anti-apoptosis (153)], tumor-linked angiogenesis (76, 191), metastasis (190), and cancer cell radioresistance (142, 143) and chemoresistance (66, 163). These topics are discussed above in this review. Because tetrac blocks T4 binding to αvβ3 and has primary anti-cancer activity in the absence of T4 (20, 60, 65, 68, 72, 194), tetrac and chemical modification of this thyroid hormone analogue have been shown in preclinical studies to have chemotherapeutic activity against a variety of human cancer cell types and xenografts of these cells (46, 194, 197, 232, 241, 275). We have pointed out that clinical elimination of host T4 in cancer-bearing patients may also improve outcome (111, 113). Because T4 is the principal ligand of the thyroid hormone receptor on αvβ3, these studies imply the involvement of the integrin in the altered tumor behavior.
As noted above, αvβ3 is modestly expressed in nonmalignant cells, or in such cells the conformation of the large extracellular domain of the integrin is one associated with low affinity for small ligands or ECM proteins (10, 83). Thus the effects of thyroid hormone analogues and particularly of tetrac in vitro on αvβ3 function in normal cells appear to be limited (H-Y. Lin and H. Y. Tang, unpublished observations), and systemic effects in the xenograft studies listed above have been minimal.
As this review points out, however, there are a number of αvβ3-mediated effects of thyroid hormone analogues on nonmalignant cells of specialized function. We have shown that platelet function is affected by T4 and tetrac (195), and the αvβ3 on platelets is a residuum of the megakaryocyte plasma membrane. Specialized bacterial phagocytosis by macrophages may be stimulated by T4 via the integrin (36). Skeletal myoblast glucose uptake may be stimulated by T4 in vitro, and this is a cell surface receptor initiated action subject to blockade by tetrac (124). Yonkers and Ribera (280) have pointed out that the receptor for thyroid hormone on αvβ3 may also be required for normal sodium current function in developing animal brain neurons.
The above observations indicate a need for a survey of αvβ3 thyroid hormone receptor relevance to functions of specific tissue cells, including immature cells, and particularly to cells of defense systems. Cytokine gene transcription in tumor cells may be affected by tetrac derivatives in tumor cells (62), as may genes for chemokines (63). Are there clinical circumstances under which the thyroid hormone analogue receptor on αvβ3 in normal immune defense cells becomes functional and subject to the effects of tetrac and T4?
The work of Hercbergs and co-workers (111, 113) suggests thyroid hormone may support the growth of certain human tumors, as do other reports dealing with spontaneous or drug-induced hypothyroidism and breast cancer (55), renal cell carcinoma (13, 227), head-and-neck cancer (198), and other cancers (21). Where such relationships can be clearly established, the thyroid hormone analogue receptor on tumor cell and endothelial cell αvβ3 is likely to be involved.
GRANTS
The authors' research cited in this review was supported in part by multiple government agencies in the United States and Taiwan and by the philanthropy of M. Frank Rudy and of Candace K. Weir.
DISCLOSURES
P. J. Davis and S. A. Mousa hold stock in a small pharmaceutical company, NanoPharmaceuticals LLC, that is developing anticancer drugs, and P. J. Davis is Chief Scientific Officer at the company. H.-Y. Lin declares no conflicts of interest, financial or otherwise.
ACKNOWLEDGMENTS
We are grateful for the collaborations over a number of years of Drs. Aleck Hercbergs (Cleveland), Osnat Ashur-Fabian (Tel Aviv), and Sandra Incerpi (Rome, Italy). This manuscript was very helpfully and extensively edited by Dr. Kelly A. Keating (Albany College of Pharmacy and Health Sciences).
REFERENCES
- 1. . Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis. Oncogene 36: 3104–3118, 2017. doi:10.1038/onc.2016.460.
Crossref | PubMed | ISI | Google Scholar - 2. . Thyroid hormone is highly permissive in angioproliferative pulmonary hypertension in rats. Eur Respir J 41: 104–114, 2013. doi:10.1183/09031936.00196511.
Crossref | PubMed | ISI | Google Scholar - 3. . Endosomes: emerging platforms for integrin-mediated FAK signalling. Trends Cell Biol 26: 391–398, 2016. doi:10.1016/j.tcb.2016.02.001.
Crossref | PubMed | ISI | Google Scholar - 4. . Pharmacological targeting of cell cycle, apoptotic and cell adhesion signaling pathways implicated in chemoresistance of cancer cells. Int J Mol Sci 19: 1690, 2018. doi:10.3390/ijms19061690.
Crossref | PubMed | ISI | Google Scholar - 5. . Stromal cells and integrins: conforming to the needs of the tumor microenvironment. Neoplasia 11: 1264–1271, 2009. doi:10.1593/neo.91302.
Crossref | PubMed | ISI | Google Scholar - 6. . Thyroid disorders in patients treated with radiotherapy for head-and-neck cancer: a retrospective analysis of seventy-three patients. Int J Radiat Oncol Biol Phys 67: 144–150, 2007. doi:10.1016/j.ijrobp.2006.08.051.
Crossref | PubMed | ISI | Google Scholar - 7. . The significance of integrin ligand nanopatterning on lipid raft clustering in hematopoietic stem cells. Biomaterials 33: 3107–3118, 2012. doi:10.1016/j.biomaterials.2012.01.002.
Crossref | PubMed | ISI | Google Scholar - 8. . Thyroid hormone receptor localization in target tissues. J Endocrinol 237: R19–R34, 2018. doi:10.1530/JOE-17-0708.
Crossref | PubMed | ISI | Google Scholar - 9. . Induction of apoptosis in T lymphoma cells by long-term treatment with thyroxine involves PKCζ nitration by nitric oxide synthase. Apoptosis 18: 1376–1390, 2013. doi:10.1007/s10495-013-0869-8.
Crossref | PubMed | ISI | Google Scholar - 10. . Integrin structure: new twists and turns in dynamic cell adhesion. Immunol Rev 186: 125–140, 2002. doi:10.1034/j.1600-065X.2002.18612.x.
Crossref | PubMed | ISI | Google Scholar - 11. . Tetrac delayed the onset of ocular melanoma in an orthotopic mouse model. Front Endocrinol (Lausanne) 9: 775, 2019. doi:10.3389/fendo.2018.00775.
Crossref | PubMed | ISI | Google Scholar - 12. . Integrins and cell metabolism: an intimate relationship impacting cancer. Int J Mol Sci 18: 189, 2017. doi:10.3390/ijms18010189.
Crossref | PubMed | ISI | Google Scholar - 13. . Correlation of degree of hypothyroidism with survival outcomes in patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors. Clin Genitourin Cancer 13: e131–e137, 2015. doi:10.1016/j.clgc.2014.11.002.
Crossref | PubMed | ISI | Google Scholar - 14. . The integrin expression profile modulates orientation and dynamics of force transmission at cell-matrix adhesions. J Cell Sci 128: 1316–1326, 2015. doi:10.1242/jcs.156950.
Crossref | PubMed | ISI | Google Scholar - 15. . Thyroid hormone binding to the rat heart cytosol proteins. Acta Physiol Pol 36: 248–255, 1985.
PubMed | Google Scholar - 16. . Cooperative nongenomic and genomic actions on thyroid hormone mediated-modulation of T cell proliferation involve up-regulation of thyroid hormone receptor and inducible nitric oxide synthase expression. J Cell Physiol 226: 3208–3218, 2011. doi:10.1002/jcp.22681.
Crossref | PubMed | ISI | Google Scholar - 17. . Prognostic significance of c-erbB2 overexpression in patients with metastatic gastric cancer. Clin Transl Oncol 15: 307–312, 2013. doi:10.1007/s12094-012-0921-0.
Crossref | PubMed | ISI | Google Scholar - 18. . αvβ3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers. Mol Cancer Ther 7: 3761–3770, 2008. doi:10.1158/1535-7163.MCT-07-2351.
Crossref | PubMed | ISI | Google Scholar - 19. . Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 146: 2864–2871, 2005. doi:10.1210/en.2005-0102.
Crossref | PubMed | ISI | Google Scholar - 20. . Tetraiodothyroacetic acid-conjugated PLGA nanoparticles: a nanomedicine approach to treat drug-resistant breast cancer. Nanomedicine (Lond) 8: 1943–1954, 2013. doi:10.2217/nnm.12.200.
Crossref | PubMed | ISI | Google Scholar - 21. . Association between new-onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor therapy in phase I clinical trials. Cancer Chemother Pharmacol 78: 167–171, 2016. doi:10.1007/s00280-016-3073-z.
Crossref | PubMed | ISI | Google Scholar - 22. . Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev Cell 3: 311–321, 2002. doi:10.1016/S1534-5807(02)00265-4.
Crossref | PubMed | ISI | Google Scholar - 23. . Involvement of phosphatidylserine, alphavbeta3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages. Arthritis Rheum 54: 927–938, 2006. doi:10.1002/art.21660.
Crossref | PubMed | Google Scholar - 24. . Functional consequences of integrin gene mutations in mice. Circ Res 89: 211–223, 2001. doi:10.1161/hh1501.094874.
Crossref | PubMed | ISI | Google Scholar - 25. . Mechanisms of thyroid hormone action. J Clin Invest 122: 3035–3043, 2012. doi:10.1172/JCI60047.
Crossref | PubMed | ISI | Google Scholar - 26. . Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol 169: 338–346, 2006. doi:10.2353/ajpath.2006.060312.
Crossref | PubMed | ISI | Google Scholar - 27. . Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients. Med Oncol 34: 68, 2017. doi:10.1007/s12032-017-0928-z.
Crossref | PubMed | ISI | Google Scholar - 28. . Activation of αvβ3 on vascular cells controls recognition of prothrombin. J Cell Biol 143: 2081–2092, 1998. doi:10.1083/jcb.143.7.2081.
Crossref | PubMed | ISI | Google Scholar - 29. . The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation. Sci Rep 7: 4656, 2017. doi:10.1038/s41598-017-04844-w.
Crossref | PubMed | ISI | Google Scholar - 30. . PKCζ, MMP-2 and MMP-9 expression in lung adenocarcinoma and association with a metastatic phenotype. Mol Med Rep 16: 8301–8306, 2017. doi:10.3892/mmr.2017.7634.
Crossref | PubMed | ISI | Google Scholar - 31. . Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol 3:
a004994 , 2011. doi:10.1101/cshperspect.a004994.
Crossref | PubMed | ISI | Google Scholar - 32. . Cytoplasm-to-nucleus shuttling of thyroid hormone receptor-β1 (Trbeta1) is directed from a plasma membrane integrin receptor by thyroid hormone. Endocr Res 34: 31–42, 2009. doi:10.1080/07435800902911810.
Crossref | PubMed | ISI | Google Scholar - 33. . Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells. Blood 125: 841–851, 2015. doi:10.1182/blood-2014-07-587337.
Crossref | PubMed | ISI | Google Scholar - 34. . The mechanisms of radioresistance in esophageal squamous cell carcinoma and current strategies in radiosensitivity. J Thorac Dis 9: 849–859, 2017. doi:10.21037/jtd.2017.03.23.
Crossref | PubMed | ISI | Google Scholar - 35. . Thyroid hormone induces sprouting angiogenesis in adult heart of hypothyroid mice through the PDGF-Akt pathway. J Cell Mol Med 16: 2726–2735, 2012. doi:10.1111/j.1582-4934.2012.01593.x.
Crossref | PubMed | ISI | Google Scholar - 36. . Thyroid hormone enhances nitric oxide-mediated bacterial clearance and promotes survival after meningococcal infection. PLoS One 7:
e41445 , 2012. doi:10.1371/journal.pone.0041445.
Crossref | PubMed | ISI | Google Scholar - 37. . Thyroid hormone-induced expression of inflammatory cytokines interfere with resveratrol-induced anti-proliferation of oral cancer cells. Food Chem Toxicol 132:
110693 , 2019. doi:10.1016/j.fct.2019.110693.
Crossref | PubMed | ISI | Google Scholar - 38. . Molecular aspects of thyroid hormone actions. Endocr Rev 31: 139–170, 2010. doi:10.1210/er.2009-0007.
Crossref | PubMed | ISI | Google Scholar - 39. . CDK11p58 inhibits ERα-positive breast cancer invasion by targeting integrin β3 via the repression of ERα signaling. BMC Cancer 14: 577, 2014. doi:10.1186/1471-2407-14-577.
Crossref | PubMed | ISI | Google Scholar - 40. . Corrigendum: Tetrac and NDAT induce anti-proliferation via integrin αvβ3 in colorectal cancers with different K-RAS status. Front Endocrinol (Lausanne) 10: 241, 2019. doi:10.3389/fendo.2019.00241.
Crossref | PubMed | ISI | Google Scholar - 41. . Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells. Endocr Relat Cancer 25: 533–545, 2018. doi:10.1530/ERC-17-0376.
Crossref | PubMed | ISI | Google Scholar - 42. . Mechanisms of dihydrotestosterone action on resveratrol-induced anti-proliferation in breast cancer cells with different ER status. Oncotarget 6: 35866–35879, 2015. doi:10.18632/oncotarget.5482.
Crossref | PubMed | Google Scholar - 44. . Role of iodine in thyroid hormones: molecular conformation of a halogen-free hormone analogue. J Med Chem 23: 584–587, 1980. doi:10.1021/jm00179a024.
Crossref | PubMed | ISI | Google Scholar - 45. . Molecular modeling of the thyroid hormone interactions with α v β 3 integrin. Steroids 72: 165–170, 2007. doi:10.1016/j.steroids.2006.11.008.
Crossref | PubMed | ISI | Google Scholar - 46. . The induction of myeloma cell death and DNA damage by tetrac, a thyroid hormone derivative. Endocr Relat Cancer 25: 21–34, 2018. doi:10.1530/ERC-17-0246.
Crossref | PubMed | ISI | Google Scholar - 47. . Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via αvβ3 integrin. Mol Cancer Res 9: 1385–1394, 2011. doi:10.1158/1541-7786.MCR-11-0187.
Crossref | PubMed | ISI | Google Scholar - 48. . Relevance of the thyroid hormones-αvβ3 pathway in primary myeloma bone marrow cells and to bortezomib action. Leuk Lymphoma 56: 1107–1114, 2015. doi:10.3109/10428194.2014.947612.
Crossref | PubMed | ISI | Google Scholar - 50. . Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 integrin in myeloma cells. Oncotarget 5: 6312–6322, 2014. doi:10.18632/oncotarget.2205.
Crossref | PubMed | Google Scholar - 52. . Endocytosis of resveratrol via lipid rafts and activation of downstream signaling pathways in cancer cells. Cancer Prev Res (Phila) 4: 1095–1106, 2011. doi:10.1158/1940-6207.CAPR-10-0274.
Crossref | PubMed | ISI | Google Scholar - 53. . HIF1α and metabolic reprogramming in inflammation. J Clin Invest 126: 3699–3707, 2016. doi:10.1172/JCI84431.
Crossref | PubMed | ISI | Google Scholar - 54. . Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression. Mol Biol Cell 16: 1901–1912, 2005. doi:10.1091/mbc.e04-12-1082.
Crossref | PubMed | ISI | Google Scholar - 55. . Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 103: 1122–1128, 2005. doi:10.1002/cncr.20881.
Crossref | PubMed | ISI | Google Scholar - 56. . Novel regulation of integrin trafficking by Rab11–FIP5 in aggressive prostate cancer. Mol Cancer Res 16: 1319–1331, 2018. doi:10.1158/1541-7786.MCR-17-0589.
Crossref | PubMed | ISI | Google Scholar - 57. . Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface. Circ Res 94: 1500–1506, 2004. doi:10.1161/01.RES.0000130784.90237.4a.
Crossref | PubMed | ISI | Google Scholar - 58. . Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells. Cancer Res 66: 7270–7275, 2006. doi:10.1158/0008-5472.CAN-05-4365.
Crossref | PubMed | ISI | Google Scholar - 59. . Cell-surface receptor for thyroid hormone and tumor cell proliferation. Expert Rev Endocrinol Metab 1: 753–761, 2006. doi:10.1586/17446651.1.6.753.
Crossref | PubMed | Google Scholar - 60. . Membrane receptor for thyroid hormone: physiologic and pharmacologic implications. Annu Rev Pharmacol Toxicol 51: 99–115, 2011. doi:10.1146/annurev-pharmtox-010510-100512.
Crossref | PubMed | ISI | Google Scholar - 61. . Cancer cell gene expression modulated from plasma membrane integrin αvβ3 by thyroid hormone and nanoparticulate tetrac. Front Endocrinol (Lausanne) 5: 240, 2015. doi:10.3389/fendo.2014.00240.
Crossref | PubMed | ISI | Google Scholar - 62. . Molecular mechanisms of actions of formulations of the thyroid hormone analogue, tetrac, on the inflammatory response. Endocr Res 38: 112–118, 2013. doi:10.3109/07435800.2013.778865.
Crossref | PubMed | ISI | Google Scholar - 63. . Actions of thyroid hormone analogues on chemokines. J Immunol Res 2016:
3147671 , 2016. doi:10.1155/2016/3147671.
Crossref | PubMed | ISI | Google Scholar - 64. . Regulation of cancer cell metabolism via the thyroid hormone analogue receptor on integrin αvβ3: actions of P-bi-TAT (tetrac-PEG) at the receptor (Poster).
AACR Metabolism and Cancer Conference .New York :September 28–October 1 , 2018, p. A48.
Google Scholar - 65. . Nongenomic actions of thyroid hormone. Nat Rev Endocrinol 12: 111–121, 2016. doi:10.1038/nrendo.2015.205.
Crossref | PubMed | ISI | Google Scholar - 66. . Thyroid hormone and P-glycoprotein in tumor cells. BioMed Res Int 2015:
168427 , 2015. doi:10.1155/2015/168427.
Crossref | PubMed | ISI | Google Scholar - 67. . Mechanisms of nongenomic actions of thyroid hormone. Front Neuroendocrinol 29: 211–218, 2008. doi:10.1016/j.yfrne.2007.09.003.
Crossref | PubMed | ISI | Google Scholar - 68. . Molecular basis of nongenomic actions of thyroid hormone. Vitam Horm 106: 67–96, 2018. doi:10.1016/bs.vh.2017.06.001.
Crossref | PubMed | ISI | Google Scholar - 69. . How thyroid hormone works depends upon cell type, receptor type, and hormone analogue: implications in cancer growth. Discov Med 27: 111–117, 2019.
PubMed | ISI | Google Scholar - 70. . Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis. OncoTargets Ther 7: 1619–1624, 2014. doi:10.2147/OTT.S67393.
Crossref | PubMed | ISI | Google Scholar - 71. . Adjunctive input to the nuclear thyroid hormone receptor from the cell surface receptor for the hormone. Thyroid 23: 1503–1509, 2013. doi:10.1089/thy.2013.0280.
Crossref | PubMed | ISI | Google Scholar - 72. . Small molecule hormone or hormone-like ligands of integrin αVβ3: implications for cancer cell behavior. Horm Cancer 4: 335–342, 2013. doi:10.1007/s12672-013-0156-8.
Crossref | PubMed | ISI | Google Scholar - 73. . New interfaces of thyroid hormone actions with blood coagulation and thrombosis. Clin Appl Thromb Hemost 24: 1014–1019, 2018. doi:10.1177/1076029618774150.
Crossref | PubMed | ISI | Google Scholar - 74. . Platelet ATP, thyroid hormone receptor on integrin αvβ3 and cancer metastasis. Horm Cancer 11: 13–16, 2020. doi:10.1007/s12672-019-00371-4.
Crossref | PubMed | ISI | Google Scholar - 75. . Thyroxine promotes association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR. J Biol Chem 275: 38032–38039, 2000. doi:10.1074/jbc.M002560200.
Crossref | PubMed | ISI | Google Scholar - 76. . Thyroid hormone, hormone analogs, and angiogenesis. Compr Physiol 6: 353–362, 2015. doi:10.1002/cphy.c150011.
Crossref | PubMed | ISI | Google Scholar - 77. . Bioactivity of thyroid hormone analogs at cancer cells. Front Endocrinol (Lausanne) 9: 739, 2018. doi:10.3389/fendo.2018.00739.
Crossref | PubMed | ISI | Google Scholar - 78. . Incomplete success of angioinhibitor therapy in cancer: Estimation of contribution of pro-angiogenic activity of patient thyroid hormone. J Cancer Sci Ther 5: 441–445, 2013. doi:10.4172/1948-5956.1000238.
Crossref | Google Scholar - 79. . Nongenomic effects of thyroid hormones on the immune system cells: new targets, old players. Steroids 77: 988–995, 2012. doi:10.1016/j.steroids.2012.02.018.
Crossref | PubMed | ISI | Google Scholar - 80. . Thyroid hormones as modulators of immune activities at the cellular level. Thyroid 21: 879–890, 2011. doi:10.1089/thy.2010.0429.
Crossref | PubMed | ISI | Google Scholar - 81. . Influence of l-thyroxine administration on poor-platelet plasma VEGF concentrations in patients with induced short-term hypothyroidism, monitored for thyroid carcinoma. Endocr J 54: 63–69, 2007. doi:10.1507/endocrj.K05-112.
Crossref | PubMed | ISI | Google Scholar - 82. . Role of membrane dynamics processes and exogenous molecules in cellular resveratrol uptake: consequences in bioavailability and activities. Mol Nutr Food Res 55: 1142–1153, 2011. doi:10.1002/mnfr.201100065.
Crossref | PubMed | ISI | Google Scholar - 83. . Integrins in cancer: biological implications and therapeutic opportunities. [Correction in Nat Rev Cancer 10: 890, 2010.] Nat Rev Cancer 10: 9–22, 2010. doi:10.1038/nrc2748.
Crossref | PubMed | ISI | Google Scholar - 84. . Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells. Oncotarget 10: 3051–3065, 2019. doi:10.18632/oncotarget.26890.
Crossref | PubMed | Google Scholar - 85. . alpha 3A beta 1 integrin localizes to focal contacts in response to diverse extracellular matrix proteins. J Cell Sci 108: 2321–2336, 1995.
Crossref | PubMed | ISI | Google Scholar - 86. . Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells. Cancer Res 72: 949–957, 2012. doi:10.1158/0008-5472.CAN-11-2371.
Crossref | PubMed | ISI | Google Scholar - 87. . Correlation of breast cancer axillary lymph node metastases with stem cell mutations. JAMA Surg 148: 873–878, 2013. doi:10.1001/jamasurg.2013.3028.
Crossref | PubMed | ISI | Google Scholar - 88. . β1Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J Clin Invest 122: 1529–1540, 2012. doi:10.1172/JCI61350.
Crossref | PubMed | ISI | Google Scholar - 89. . Low thyroid hormone levels improve survival in murine model for ocular melanoma. Oncotarget 6: 11038–11046, 2015. doi:10.18632/oncotarget.3566.
Crossref | PubMed | Google Scholar - 90. . Nonthyroidal illness syndrome. Curr Opin Endocrinol Diabetes Obes 20: 478–484, 2013. doi:10.1097/01.med.0000433069.09294.e8.
Crossref | PubMed | Google Scholar - 91. . Regulation of cerebellar neuronal migration and neurite outgrowth by thyroxine and 3,3′,5′-triiodothyronine. Brain Res Dev Brain Res 154: 121–135, 2005. doi:10.1016/j.devbrainres.2004.07.016.
Crossref | PubMed | Google Scholar - 92. .
Extranuclear actions of thyroid hormone in the brain . In: Recent Research Developments in Neuroendocrinology—Thyroid Hormone and Brain Maturation, edited by Porterfield SP, Hendrich CE. Trivandrum, India: Research Signpost, 1997, p. 113–130.
Google Scholar - 93. . Vitronectin and its receptors. Curr Opin Cell Biol 5: 864–868, 1993. doi:10.1016/0955-0674(93)90036-P.
Crossref | PubMed | ISI | Google Scholar - 94. . miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. Mol Cancer 12: 130, 2013. doi:10.1186/1476-4598-12-130.
Crossref | PubMed | ISI | Google Scholar - 95. . Thyroid hormone controls breast cancer cell movement via integrin αV/β3/SRC/FAK/PI3-kinases. Horm Cancer 8: 16–27, 2017. doi:10.1007/s12672-016-0280-3.
Crossref | PubMed | ISI | Google Scholar - 96. . Combined QM/MM study of thyroid and steroid hormone analogue interactions with αvβ3 integrin. J Biomed Biotechnol 2012:
959057 , 2012. doi:10.1155/2012/959057.
Crossref | PubMed | Google Scholar - 97. . Glioma derived isocitrate dehydrogenase-2 mutations induced up-regulation of HIF-1α and β-catenin signaling: possible impact on glioma cell metastasis and chemo-resistance. Int J Biochem Cell Biol 44: 770–775, 2012. doi:10.1016/j.biocel.2012.01.017.
Crossref | PubMed | ISI | Google Scholar - 98. . Redistribution and dysfunction of integrins in cultured renal epithelial cells exposed to oxidative stress. Am J Physiol 264: F149–F157, 1993. doi:10.1152/ajprenal.1993.264.1.F149.
Link | ISI | Google Scholar - 99. . Identification of cell culture conditions to control N-glycosylation site-occupancy of recombinant glycoproteins expressed in CHO cells. Biotechnol Bioeng 103: 1164–1175, 2009. doi:10.1002/bit.22348.
Crossref | PubMed | ISI | Google Scholar - 100. . RGD binding to integrin alphavbeta3 affects cell motility and adhesion in primary human breast cancer cultures. Ultrastruct Pathol 36: 387–399, 2012. doi:10.3109/01913123.2012.681834.
Crossref | PubMed | ISI | Google Scholar - 101. . αvβ3-integrin is a major sensor and activator of innate immunity to herpes simplex virus-1. Proc Natl Acad Sci USA 109: 19792–19797, 2012. doi:10.1073/pnas.1212597109.
Crossref | PubMed | ISI | Google Scholar - 102. . Modification of survival pathway gene expression in human breast cancer cells by tetraiodothyroacetic acid (tetrac). Cell Cycle 8: 3562–3570, 2009. doi:10.4161/cc.8.21.9963.
Crossref | PubMed | ISI | Google Scholar - 103. . 3,5,3′Triiodo-l-thyronine induces SREBP-1 expression by non-genomic actions in human HEP G2 cells. J Cell Physiol 227: 2388–2397, 2012. doi:10.1002/jcp.22974.
Crossref | PubMed | ISI | Google Scholar - 104. . Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. Lancet Diabetes Endocrinol 7: 695–706, 2019. doi:10.1016/S2213-8587(19)30155-X.
Crossref | PubMed | ISI | Google Scholar - 105. . Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis. Mol Cancer 11: 66, 2012. doi:10.1186/1476-4598-11-66.
Crossref | PubMed | ISI | Google Scholar - 106. . Lysine metabolism in mammalian brain: an update on the importance of recent discoveries. Amino Acids 45: 1249–1272, 2013. doi:10.1007/s00726-013-1590-1.
Crossref | PubMed | ISI | Google Scholar - 107. . Overlapping nongenomic and genomic actions of thyroid hormone and steroids. Best Pract Res Clin Endocrinol Metab 29: 581–593, 2015. doi:10.1016/j.beem.2015.04.001.
Crossref | PubMed | ISI | Google Scholar - 108. . A molecular view of the radioresistance of gliomas. Oncotarget 8: 100931–100941, 2017. doi:10.18632/oncotarget.21753.
Crossref | PubMed | Google Scholar - 109. . The role of integrin αVβ3 in osteocyte mechanotransduction. J Mech Behav Biomed Mater 42: 67–75, 2015. doi:10.1016/j.jmbbm.2014.11.001.
Crossref | PubMed | ISI | Google Scholar - 110. . Radiosensitization of GL261 glioma cells by tetraiodothyroacetic acid (tetrac). Cell Cycle 8: 2586–2591, 2009. doi:10.4161/cc.8.16.9328.
Crossref | PubMed | ISI | Google Scholar - 111. . Medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: an observational study. Oncologist 20: 72–76, 2015. doi:10.1634/theoncologist.2014-0308.
Crossref | PubMed | ISI | Google Scholar - 112. . Nonthyroidal illness syndrome and thyroid hormone actions at integrin αvβ3. J Clin Endocrinol Metab 103: 1291–1295, 2018. doi:10.1210/jc.2017-01939.
Crossref | PubMed | ISI | Google Scholar - 113. . Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study. Anticancer Res 23, 1B: 617–626, 2003.
PubMed | ISI | Google Scholar - 114. . Radiosensitization and production of DNA double-strand breaks in U87MG brain tumor cells induced by tetraiodothyroacetic acid (tetrac). Cell Cycle 10: 352–357, 2011. doi:10.4161/cc.10.2.14641.
Crossref | PubMed | ISI | Google Scholar - 115. . Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci USA 103: 14104–14109, 2006. doi:10.1073/pnas.0601600103.
Crossref | PubMed | ISI | Google Scholar - 116. . Resveratrol inhibits human leiomyoma cell proliferation via crosstalk between integrin αvβ3 and IGF-1R. Food Chem Toxicol 120: 346–355, 2018. doi:10.1016/j.fct.2018.07.030.
Crossref | PubMed | ISI | Google Scholar - 117. . T-cell integrins: more than just sticking points. J Cell Sci 116: 4695–4705, 2003. doi:10.1242/jcs.00876.
Crossref | PubMed | ISI | Google Scholar - 118. . Triangle of AKT2, miRNA, and tumorigenesis in different cancers. Appl Biochem Biotechnol 185: 524–540, 2018. doi:10.1007/s12010-017-2657-3.
Crossref | PubMed | ISI | Google Scholar - 119. . Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells. Oncotarget 8: 24237–24249, 2017. doi:10.18632/oncotarget.10757.
Crossref | PubMed | Google Scholar - 120. . Regulation of p53 and cell proliferation by resveratrol and its derivatives in breast cancer cells: an in silico and biochemical approach targeting integrin αvβ3. Int J Cancer 129: 2732–2743, 2011. doi:10.1002/ijc.25930.
Crossref | PubMed | ISI | Google Scholar - 121. . Shear-induced CCN1 promotes atheroprone endothelial phenotypes and atherosclerosis. Circulation 139: 2877–2891, 2019. doi:10.1161/CIRCULATIONAHA.118.033895.
Crossref | PubMed | ISI | Google Scholar - 122. . Integrin structure. Biochem Soc Trans 28: 311–340, 2000. doi:10.1042/bst0280311.
Crossref | PubMed | ISI | Google Scholar - 123. . Integrins: bidirectional, allosteric signaling machines. Cell 110: 673–687, 2002. doi:10.1016/S0092-8674(02)00971-6.
Crossref | PubMed | ISI | Google Scholar - 124. . Thyroid hormone inhibition in L6 myoblasts of IGF-I-mediated glucose uptake and proliferation: new roles for integrin αvβ3. Am J Physiol Cell Physiol 307: C150–C161, 2014. doi:10.1152/ajpcell.00308.2013.
Link | ISI | Google Scholar - 125. . The three receptor tyrosine kinases c-KIT, VEGFR2 and PDGFRα, closely spaced at 4q12, show increased protein expression in triple-negative breast cancer. PLoS One 9:
e102176 , 2014. doi:10.1371/journal.pone.0102176.
Crossref | PubMed | Google Scholar - 126. . Modulating the function of the immune system by thyroid hormones and thyrotropin. Immunol Lett 184: 76–83, 2017. doi:10.1016/j.imlet.2017.02.010.
Crossref | PubMed | ISI | Google Scholar - 127. . Dysregulation of AKT1, a miR-138 target gene, is involved in the migration and invasion of tongue squamous cell carcinoma. J Oral Pathol Med 46: 731–737, 2017. doi:10.1111/jop.12551.
Crossref | PubMed | ISI | Google Scholar - 128. . Evidence that phosphorylation events participate in thyroid hormone action. Endocrinology 134: 543–548, 1994. doi:10.1210/endo.134.2.8299553.
Crossref | PubMed | ISI | Google Scholar - 129. . Hypoxia selectively enhances integrin α5β1 receptor expression in breast cancer to promote metastasis. Mol Cancer Res 15: 723–734, 2017. doi:10.1158/1541-7786.MCR-16-0338.
Crossref | PubMed | ISI | Google Scholar - 130. . c-Kit expression as a prognostic molecular marker in patients with basal-like breast cancer. Br J Surg 100: 490–496, 2013. doi:10.1002/bjs.9021.
Crossref | PubMed | ISI | Google Scholar - 131. . Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase. Proc Natl Acad Sci USA 86: 7861–7865, 1989. doi:10.1073/pnas.86.20.7861.
Crossref | PubMed | ISI | Google Scholar - 132. . Functional regulation of thyroid hormone receptor variant TR alpha 2 by phosphorylation. Mol Cell Biol 15: 2341–2348, 1995. doi:10.1128/MCB.15.5.2341.
Crossref | PubMed | ISI | Google Scholar - 133. . Alpha6-integrin regulates FGFR1 expression through the ZEB1/YAP1 transcription complex in glioblastoma stem cells resulting in enhanced proliferation and stemness. Cancers (Basel) 11: 406, 2019. doi:10.3390/cancers11030406.
Crossref | PubMed | ISI | Google Scholar - 134. . Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy. Clin Cancer Res 18: 4365–4374, 2012. doi:10.1158/1078-0432.CCR-11-3028.
Crossref | PubMed | ISI | Google Scholar - 135. . Thyroid hormone effect on human mitochondria measured by flow cytometry. Scand J Clin Lab Invest 69: 772–776, 2009. doi:10.3109/00365510903154752.
Crossref | PubMed | ISI | Google Scholar - 136. . Platelet integrins in tumor metastasis: do they represent a therapeutic target? Cancers (Basel) 9: 133, 2017. doi:10.3390/cancers9100133.
Crossref | PubMed | ISI | Google Scholar - 137. . Thyroid hormone stimulates release of calmodulin-enhancing activity from human erythrocyte membranes in vitro. Clin Sci (Lond) 84: 217–223, 1993. doi:10.1042/cs0840217.
Crossref | PubMed | ISI | Google Scholar - 138. . Integrin α2 marks a niche of trophoblast progenitor cells in first trimester human placenta. Development 145:
dev162305 , 2018. doi:10.1242/dev.162305.
Crossref | PubMed | ISI | Google Scholar - 139. . Thyroid hormone promotes β-catenin activation and cell proliferation in colorectal cancer. Horm Cancer 9: 156–165, 2018. doi:10.1007/s12672-018-0324-y.
Crossref | PubMed | ISI | Google Scholar - 140. . Src kinase integrates PI3K/Akt and MAPK/ERK1/2 pathways in T3-induced Na-K-ATPase activity in adult rat alveolar cells. Am J Physiol Lung Cell Mol Physiol 301: L765–L771, 2011. doi:10.1152/ajplung.00151.2011.
Link | ISI | Google Scholar - 141. . In vitro effects of tetraiodothyroacetic acid combined with X-irradiation on basal cell carcinoma cells. Cell Cycle 16: 367–373, 2017. doi:10.1080/15384101.2016.1269044.
Crossref | PubMed | ISI | Google Scholar - 142. . Activation of tumor cell integrin αvβ3 by radiation and reversal of activation by chemically modified tetraiodothyroacetic acid (tetrac). Endocr Res 43: 215–219, 2018. doi:10.1080/07435800.2018.1456550.
Crossref | PubMed | ISI | Google Scholar - 143. . Radioresistance of cancer cells, integrin αvβ3 and thyroid hormone. Oncotarget 9: 37069–37075, 2018. doi:10.18632/oncotarget.26434.
Crossref | PubMed | Google Scholar - 144. . Thyroid hormone activation of transcription is potentiated by activators of cAMP-dependent protein kinase. J Biol Chem 271: 21950–21955, 1996. doi:10.1074/jbc.271.36.21950.
Crossref | PubMed | ISI | Google Scholar - 145. . Cytosolic thyroxine-binding protein and brain development. Mol Cell Endocrinol 18: 201–214, 1980. doi:10.1016/0303-7207(80)90066-0.
Crossref | PubMed | ISI | Google Scholar - 146. . Non-genomic actions of thyroid hormone in brain development. Steroids 73: 1008–1012, 2008. doi:10.1016/j.steroids.2007.12.016.
Crossref | PubMed | ISI | Google Scholar - 147. . Significance of PI3K/AKT signaling pathway in metastasis of esophageal squamous cell carcinoma and its potential as a target for anti-metastasis therapy. Oncotarget 8: 38755–38766, 2017. doi:10.18632/oncotarget.16333.
Crossref | PubMed | Google Scholar - 148. . Study on the effect of Integrin αVβ6 on proliferation and apoptosis of cervical cancer cells. Eur Rev Med Pharmacol Sci 21: 2811–2815, 2017.
PubMed | ISI | Google Scholar - 149. . Organ-specific effects of 3,5,3′-triiodothyroacetic acid in rats. Eur J Endocrinol 137: 537–544, 1997. doi:10.1530/eje.0.1370537.
Crossref | PubMed | ISI | Google Scholar - 150. . Interaction of kindlin-2 with integrin β3 promotes outside-in signaling responses by the αVβ3 vitronectin receptor. Blood 125: 1995–2004, 2015. doi:10.1182/blood-2014-09-603035.
Crossref | PubMed | ISI | Google Scholar - 151. . Actions of l-thyroxine and Nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells. Steroids 114: 59–67, 2016. doi:10.1016/j.steroids.2016.05.006.
Crossref | PubMed | ISI | Google Scholar - 152. . In tumor cells, thyroid hormone analogues non-immunologically regulate PD-L1 and PD-1 accumulation that is anti-apoptotic. Oncotarget 9: 34033–34037, 2018. doi:10.18632/oncotarget.26143.
Crossref | PubMed | Google Scholar - 153. . Thyroid hormone, cancer, and apoptosis. Compr Physiol 6: 1221–1237, 2016. doi:10.1002/cphy.c150035.
Crossref | PubMed | ISI | Google Scholar - 154. . Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells. Am J Physiol Cell Physiol 276: C1014–C1024, 1999. doi:10.1152/ajpcell.1999.276.5.C1014.
Link | ISI | Google Scholar - 155. . Molecular basis for certain neuroprotective effects of thyroid hormone. Front Mol Neurosci 4: 29, 2011. doi:10.3389/fnmol.2011.00029.
Crossref | PubMed | ISI | Google Scholar - 156. . The pro-apoptotic action of stilbene-induced COX-2 in cancer cells: convergence with the anti-apoptotic effect of thyroid hormone. Cell Cycle 8: 1877–1882, 2009. doi:10.4161/cc.8.12.8747.
Crossref | PubMed | ISI | Google Scholar - 157. . Thyroid hormone and anti-apoptosis in tumor cells. Oncotarget 6: 14735–14743, 2015. doi:10.18632/oncotarget.4023.
Crossref | PubMed | Google Scholar - 158. . Integrin alphaVbeta3 contains a receptor site for resveratrol. FASEB J 20: 1742–1744, 2006. doi:10.1096/fj.06-5743fje.
Crossref | PubMed | ISI | Google Scholar - 159. . Potentiation by thyroid hormone of human IFN-gamma-induced HLA-DR expression. J Immunol 161: 843–849, 1998.
PubMed | ISI | Google Scholar - 160. . Nuclear monomeric integrin αv in cancer cells is a coactivator regulated by thyroid hormone. FASEB J 27: 3209–3216, 2013. doi:10.1096/fj.12-227132.
Crossref | PubMed | ISI | Google Scholar - 161. . Androgen-induced human breast cancer cell proliferation is mediated by discrete mechanisms in estrogen receptor-α-positive and -negative breast cancer cells. J Steroid Biochem Mol Biol 113: 182–188, 2009. doi:10.1016/j.jsbmb.2008.12.010.
Crossref | PubMed | ISI | Google Scholar - 162. . l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 296: C980–C991, 2009. doi:10.1152/ajpcell.00305.2008.
Link | ISI | Google Scholar - 163. . Nongenomic regulation by thyroid hormone of plasma membrane ion and small molecule pumps. Discov Med 14: 199–206, 2012.
PubMed | ISI | Google Scholar - 164. . Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: both actions are integrin and ERK mediated. Carcinogenesis 29: 62–69, 2008. doi:10.1093/carcin/bgm239.
Crossref | PubMed | ISI | Google Scholar - 165. . Action of reverse T3 on cancer cells. Endocr Res 44: 148–152, 2019. doi:10.1080/07435800.2019.1600536.
Crossref | PubMed | ISI | Google Scholar - 166. . Thyroid hormone is a MAPK-dependent growth factor for thyroid cancer cells and is anti-apoptotic. Steroids 72: 180–187, 2007. doi:10.1016/j.steroids.2006.11.014.
Crossref | PubMed | ISI | Google Scholar - 167. . Thyroid hormone analogues potentiate the antiviral action of interferon-γ by two mechanisms. J Cell Physiol 167: 269–276, 1996. doi:10.1002/(SICI)1097-4652(199605)167:2<269:AID-JCP10>3.0.CO;2-3.
Crossref | PubMed | ISI | Google Scholar - 168. . Potentiation by thyroxine of interferon-γ-induced HLA-DR expression is protein kinase A- and C-dependent. J Interferon Cytokine Res 16: 17–24, 1996. doi:10.1089/jir.1996.16.17.
Crossref | PubMed | ISI | Google Scholar - 169. . Mechanism of cancer cell adaptation to metabolic stress: proteomics identification of a novel thyroid hormone-mediated gastric carcinogenic signaling pathway. Mol Cell Proteomics 8: 70–85, 2009. doi:10.1074/mcp.M800195-MCP200.
Crossref | PubMed | Google Scholar - 170. . Structural basis of integrin regulation and signaling. Annu Rev Immunol 25: 619–647, 2007. doi:10.1146/annurev.immunol.25.022106.141618.
Crossref | PubMed | ISI | Google Scholar - 171. . Regulation of pulmonary inflammation and fibrosis through expression of integrins alphaVbeta3 and alphaVbeta5 on pulmonary T lymphocytes. Arthritis Rheum 60: 1530–1539, 2009. doi:10.1002/art.24435.
Crossref | PubMed | Google Scholar - 172. . Hypoxia and HIF pathway in cancer and the placenta. Placenta 56: 8–13, 2017. doi:10.1016/j.placenta.2017.03.010.
Crossref | PubMed | ISI | Google Scholar - 173. . MMP-2 suppression abrogates irradiation-induced microtubule formation in endothelial cells by inhibiting αvβ3-mediated SDF-1/CXCR4 signaling. Int J Oncol 42: 1279–1288, 2013. doi:10.3892/ijo.2013.1806.
Crossref | PubMed | ISI | Google Scholar - 174. . Effect of triiodothyronine on reactive oxygen species generation by leukocytes, indices of oxidative damage, and antioxidant reserve. Metabolism 49: 799–803, 2000. doi:10.1053/meta.2000.6263.
Crossref | PubMed | ISI | Google Scholar - 175. . Bone-induced c-kit expression in prostate cancer: a driver of intraosseous tumor growth. Int J Cancer 136: 11–20, 2015. doi:10.1002/ijc.28948.
Crossref | PubMed | ISI | Google Scholar - 176. . Kindlins in FERM adhesion. Blood 115: 4011–4017, 2010. doi:10.1182/blood-2009-10-239269.
Crossref | PubMed | ISI | Google Scholar - 177. . MiR-495 inhibits esophageal squamous cell carcinoma progression by targeting Akt1. Oncotarget 7: 51223–51236, 2016. doi:10.18632/oncotarget.9981.
Crossref | PubMed | Google Scholar - 178. . A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology 155: 3713–3724, 2014. doi:10.1210/en.2013-2058.
Crossref | PubMed | ISI | Google Scholar - 179. . Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis. Am J Physiol Endocrinol Metab 294: E688–E697, 2008. doi:10.1152/ajpendo.00417.2007.
Link | ISI | Google Scholar - 180. . Crosstalk between integrin αvβ3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells. PLoS One 6:
e27547 , 2011. doi:10.1371/journal.pone.0027547.
Crossref | PubMed | ISI | Google Scholar - 181. . Resveratrol inhibits ovarian cancer cell adhesion to peritoneal mesothelium in vitro by modulating the production of α5β1 integrins and hyaluronic acid. Gynecol Oncol 134: 624–630, 2014. doi:10.1016/j.ygyno.2014.06.022.
Crossref | PubMed | ISI | Google Scholar - 182. . Thyroid hormone mediated changes in gene expression can be initiated by cytosolic action of the thyroid hormone receptor β through the phosphatidylinositol 3-kinase pathway. Nucl Recept Signal 4:
nrs.04020 , 2006. doi:10.1621/nrs.04020.
Crossref | PubMed | Google Scholar - 183. . Stanniocalcin 1 induction by thyroid hormone depends on thyroid hormone receptor β and phosphatidylinositol 3-kinase activation. Exp Clin Endocrinol Diabetes 119: 81–85, 2011. doi:10.1055/s-0030-1262860.
Crossref | PubMed | ISI | Google Scholar - 184. . Wound healing properties of cimetidine in vitro. Drug Intell Clin Pharm 20: 973–975, 1986. doi:10.1177/106002808602001212.
Crossref | PubMed | Google Scholar - 185. . Gonadotropin-releasing hormone agonists reduce the migratory and the invasive behavior of androgen-independent prostate cancer cells by interfering with the activity of IGF-I. Int J Oncol 30: 261–271, 2007. doi:10.3892/ijo.30.1.261.
Crossref | PubMed | ISI | Google Scholar - 186. . Integrin trafficking in cells and tissues. Nat Cell Biol 21: 122–132, 2019. doi:10.1038/s41556-018-0223-z.
Crossref | PubMed | ISI | Google Scholar - 187. . Role of the orphan nuclear receptor ROR α in the control of the metastatic behavior of androgen-independent prostate cancer cells. Oncol Rep 9: 1139–1143, 2002.
PubMed | ISI | Google Scholar - 188. . Tetraiodothyroacetic acid, a small molecule integrin ligand, blocks angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor. Angiogenesis 11: 183–190, 2008. doi:10.1007/s10456-007-9088-7.
Crossref | PubMed | ISI | Google Scholar - 189. . Pro-angiogenesis action of thyroid hormone and analogs in a three-dimensional in vitro microvascular endothelial sprouting model. Int Angiol 25: 407–413, 2006.
PubMed | ISI | Google Scholar - 190. . Contributions of thyroid hormone to cancer metastasis. Biomedicines 6: 89, 2018. doi:10.3390/biomedicines6030089.
Crossref | PubMed | ISI | Google Scholar - 191. . Modulation of angiogenesis by thyroid hormone and hormone analogues: implications for cancer management. Angiogenesis 17: 463–469, 2014. doi:10.1007/s10456-014-9418-5.
Crossref | PubMed | ISI | Google Scholar - 192. . Proangiogenesis action of the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) is initiated at the cell surface and is integrin mediated. Endocrinology 147: 1602–1607, 2006. doi:10.1210/en.2005-1390.
Crossref | PubMed | ISI | Google Scholar - 193. . MicroRNA-21 and microRNA-15A expression in human breast cancer (MDA-MB-231) cells exposed to nanoparticulate tetraiodothyroacetic acid (Nanotetrac) (Abstract). Endocr Rev 35, Suppl 1:
SUN-0472 , 2014. doi:10.1093/edrv/35.supp.1.
Crossref | ISI | Google Scholar - 194. . Tetraiodothyroacetic acid and its nanoformulation inhibit thyroid hormone stimulation of non-small cell lung cancer cells in vitro and its growth in xenografts. Lung Cancer 76: 39–45, 2012. doi:10.1016/j.lungcan.2011.10.003.
Crossref | PubMed | ISI | Google Scholar - 195. . Human platelet aggregation and degranulation is induced in vitro by l-thyroxine, but not by 3,5,3′-triiodo-l-thyronine or diiodothyropropionic acid (DITPA). Clin Appl Thromb Hemost 16: 288–293, 2010. doi:10.1177/1076029609348315.
Crossref | PubMed | ISI | Google Scholar - 196. . Implantation-dependent expression of trophinin by maternal fallopian tube epithelia during tubal pregnancies: possible role of human chorionic gonadotrophin on ectopic pregnancy. Am J Pathol 163: 2211–2219, 2003. doi:10.1016/S0002-9440(10)63579-1.
Crossref | PubMed | ISI | Google Scholar - 197. . Tetrac downregulates β-catenin and HMGA2 to promote the effect of resveratrol in colon cancer. Endocr Relat Cancer 25: 279–293, 2018. doi:10.1530/ERC-17-0450.
Crossref | PubMed | ISI | Google Scholar - 198. . Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 132: 1041–1046, 2006. doi:10.1001/archotol.132.10.1041.
Crossref | PubMed | Google Scholar - 199. . Thyroid hormone regulates the expression and function of P-glycoprotein in Caco-2 cells. Pharm Res 25: 1037–1042, 2008. doi:10.1007/s11095-007-9495-x.
Crossref | PubMed | ISI | Google Scholar - 200. . A cytoplasmic thyroid hormone binding protein: characterization using monoclonal antibodies. Biochemistry 28: 617–623, 1989. doi:10.1021/bi00428a030.
Crossref | PubMed | ISI | Google Scholar - 201. . Gene expression profiling of the anti-glioma effect of Cilengitide. Springerplus 2: 160, 2013. doi:10.1186/2193-1801-2-160.
Crossref | PubMed | Google Scholar - 202. . αV integrin induces multicellular radioresistance in human nasopharyngeal carcinoma via activating SAPK/JNK pathway. PLoS One 7:
e38737 , 2012. doi:10.1371/journal.pone.0038737.
Crossref | PubMed | ISI | Google Scholar - 203. . Oncogenic mutations of thyroid hormone receptor β. Oncotarget 6: 8115–8131, 2015. doi:10.18632/oncotarget.3466.
Crossref | PubMed | Google Scholar - 204. . Requirement for and polarized localization of integrin proteins during Drosophila wound closure. Mol Biol Cell 29: 2137–2147, 2018. doi:10.1091/mbc.E17-11-0635.
Crossref | PubMed | ISI | Google Scholar - 205. . α6 Integrin cleavage: sensitizing human prostate cancer to ionizing radiation. Int J Radiat Biol 83: 761–767, 2007. doi:10.1080/09553000701633135.
Crossref | PubMed | ISI | Google Scholar - 206. . The hypoxic tumour microenvironment. Oncogenesis 7: 10, 2018. doi:10.1038/s41389-017-0011-9.
Crossref | PubMed | ISI | Google Scholar - 207. . Ligand binding to integrins. J Biol Chem 275: 21785–21788, 2000. doi:10.1074/jbc.R000003200.
Crossref | PubMed | ISI | Google Scholar - 208. . Integrin function in vascular biology: a view from 2013. Curr Opin Hematol 21: 241–247, 2014. doi:10.1097/MOH.0000000000000042.
Crossref | PubMed | ISI | Google Scholar - 209. . Delineating the underlying molecular mechanisms and key genes involved in metastasis of colorectal cancer via bioinformatics analysis. Oncol Rep 39: 2297–2305, 2018. doi:10.3892/or.2018.6303.
Crossref | PubMed | ISI | Google Scholar - 210. . Expression of integrins and extracellular matrix proteins at the maternal-fetal interface during tubal implantation. Reproduction 126: 383–391, 2003. doi:10.1530/rep.0.1260383.
Crossref | PubMed | ISI | Google Scholar - 211. . The MKK7 p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese. PLoS Genet 12:
e1005955 , 2016. doi:10.1371/journal.pgen.1005955.
Crossref | PubMed | ISI | Google Scholar - 212. . Kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch in the integrin outside-in signaling circuit. J Biol Chem 289: 31001–31013, 2014. doi:10.1074/jbc.M114.580811.
Crossref | PubMed | ISI | Google Scholar - 213. . Ligand-occupied integrin internalization links nutrient signaling to invasive migration. Cell Rep 10: 398–413, 2015. doi:10.1016/j.celrep.2014.12.037.
Crossref | PubMed | ISI | Google Scholar - 214. . Triazole modified tetraiodothyroacetic acid conjugated to polyethylene glycol: high affinity thyrointegrin αvβ3 antagonist with potent anticancer activities in glioblastoma multiforme. Bioconjug Chem 30: 3087–3097, 2019. doi:10.1021/acs.bioconjchem.9b00742.
Crossref | PubMed | ISI | Google Scholar - 215. . A specific l-tri-iodothyronine-binding protein in the cytosol fraction of human breast adipose tissue. Biochem J 206: 19–25, 1982.
Crossref | PubMed | ISI | Google Scholar - 216. . Regulation of cell migration and β1 integrin trafficking by the endosomal adaptor GGA3. Traffic 17: 670–688, 2016. doi:10.1111/tra.12390.
Crossref | PubMed | ISI | Google Scholar - 217. . Hematopoiesis. Cold Spring Harb Perspect Biol 4:
a008250 , 2012. doi:10.1101/cshperspect.a008250.
Crossref | PubMed | ISI | Google Scholar - 218. . AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins. Sci Rep 7: 44244, 2017. doi:10.1038/srep44244.
Crossref | PubMed | ISI | Google Scholar - 219. . Function and dynamics of tetraspanins during antigen recognition and immunological synapse formation. Front Immunol 6: 653, 2016. doi:10.3389/fimmu.2015.00653.
Crossref | PubMed | ISI | Google Scholar - 220. . The kindlin family: functions, signaling properties and implications for human disease. J Cell Sci 129: 17–27, 2016. doi:10.1242/jcs.161190.
Crossref | PubMed | ISI | Google Scholar - 221. . Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 513: 110–114, 2014. doi:10.1038/nature13441.
Crossref | PubMed | ISI | Google Scholar - 222. . Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells. Int J Oncol 50: 5–14, 2017. doi:10.3892/ijo.2016.3771.
Crossref | PubMed | ISI | Google Scholar - 223. . MKK7 mediates miR-493-dependent suppression of liver metastasis of colon cancer cells. Cancer Sci 105: 425–430, 2014. doi:10.1111/cas.12380.
Crossref | PubMed | ISI | Google Scholar - 224. . Gastrointestinal stromal tumors: a multidisciplinary challenge. World J Gastroenterol 24: 1925–1941, 2018. doi:10.3748/wjg.v24.i18.1925.
Crossref | PubMed | ISI | Google Scholar - 225. . Hypothyroidism in pancreatic cancer: Role of exogenous thyroid hormone in tumor invasion-preliminary observations. J Thyroid Res 2016:
2454989 , 2016. doi:10.1155/2016/2454989.
Crossref | PubMed | ISI | Google Scholar - 226. . A report of hypothyroidism induced by an over-the-counter fat loss supplement (Tiratricol). Int J Sport Nutr Exerc Metab 13: 112–116, 2003. doi:10.1123/ijsnem.13.1.112.
Crossref | PubMed | ISI | Google Scholar - 227. . Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 117: 534–544, 2011. doi:10.1002/cncr.25422.
Crossref | PubMed | ISI | Google Scholar - 228. . Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol 25: 234–240, 2015. doi:10.1016/j.tcb.2014.12.006.
Crossref | PubMed | ISI | Google Scholar - 229. . Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signaling and malignant features in vitro and in vivo. Oncotarget 8: 114856–114876, 2017. doi:10.18632/oncotarget.23145.
Crossref | PubMed | Google Scholar - 230. . Inside-out, outside-in, and inside-outside-in: G protein signaling in integrin-mediated cell adhesion, spreading, and retraction. Curr Opin Cell Biol 24: 600–606, 2012. doi:10.1016/j.ceb.2012.08.011.
Crossref | PubMed | ISI | Google Scholar - 231. . Integrin β3 prevents apoptosis of HL-1 cardiomyocytes under conditions of oxidative stress. Can J Physiol Pharmacol 88: 324–330, 2010. doi:10.1139/Y09-131.
Crossref | PubMed | ISI | Google Scholar - 232. . Thyroid hormones derivatives reduce proliferation and induce cell death and DNA damage in ovarian cancer. Sci Rep 7: 16475, 2017. doi:10.1038/s41598-017-16593-x.
Crossref | PubMed | ISI | Google Scholar - 233. . The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation. Oncogene 35: 1977–1987, 2016. doi:10.1038/onc.2015.262.
Crossref | PubMed | ISI | Google Scholar - 234. . Thyroxine-dependent modulation of actin polymerization in cultured astrocytes. A novel, extranuclear action of thyroid hormone. J Biol Chem 265: 5296–5302, 1990.
Crossref | PubMed | ISI | Google Scholar - 235. . Regulation of expression of the Na+/H+ exchanger by thyroid hormone. Vitam Horm 69: 249–269, 2004. doi:10.1016/S0083-6729(04)69009-1.
Crossref | PubMed | ISI | Google Scholar - 236. . Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer 127: 394–403, 2010. doi:10.1002/ijc.24715.
Crossref | PubMed | ISI | Google Scholar - 237. . Clustering of integrin α5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells. Mol Biol Cell 28: 1288–1300, 2017. doi:10.1091/mbc.e16-12-0852.
Crossref | PubMed | ISI | Google Scholar - 238. . The migration of fibroblasts into an in vitro wound. Br J Exp Pathol 60: 582–588, 1979.
PubMed | Google Scholar - 239. . Absence of integrin αvβ3 enhances vascular leak in mice by inhibiting endothelial cortical actin formation. Am J Respir Crit Care Med 185: 58–66, 2012. doi:10.1164/rccm.201108-1381OC.
Crossref | PubMed | ISI | Google Scholar - 240. . Integrin β3 inhibits hypoxia-induced apoptosis in cardiomyocytes. Acta Biochim Biophys Sin (Shanghai) 50: 658–665, 2018. doi:10.1093/abbs/gmy056.
Crossref | PubMed | ISI | Google Scholar - 241. . Nanoparticulate tetrac inhibits growth and vascularity of glioblastoma xenografts. Horm Cancer 8: 157–165, 2017. doi:10.1007/s12672-017-0293-6.
Crossref | PubMed | ISI | Google Scholar - 242. . Targeted delivery of cisplatin to tumor xenografts via the nanoparticle component of nano-diamino-tetrac. Nanomedicine (Lond) 12: 195–205, 2017. doi:10.2217/nnm-2016-0315.
Crossref | PubMed | ISI | Google Scholar - 243. . Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac. Int J Nanomedicine 12: 1305–1315, 2017. doi:10.2147/IJN.S123742.
Crossref | PubMed | ISI | Google Scholar - 244. . Integrin activation by talin, kindlin and mechanical forces. Nat Cell Biol 21: 25–31, 2019. doi:10.1038/s41556-018-0234-9.
Crossref | PubMed | ISI | Google Scholar - 245. . μ-Crystallin, a NADPH-dependent T3-binding protein in cytosol. Trends Endocrinol Metab 18: 286–289, 2007. doi:10.1016/j.tem.2007.07.002.
Crossref | PubMed | ISI | Google Scholar - 246. . Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions. Proc Natl Acad Sci USA 114: 10648–10653, 2017. doi:10.1073/pnas.1701136114.
Crossref | PubMed | ISI | Google Scholar - 247. . The biological functions of β3 integrins. Folia Biol (Praha) 50: 143–152, 2004.
PubMed | ISI | Google Scholar - 248. . The integrins. Genome Biol 8: 215, 2007. doi:10.1186/gb-2007-8-5-215.
Crossref | PubMed | ISI | Google Scholar - 249. . C-kit signaling promotes proliferation and invasion of colorectal mucinous adenocarcinoma in a murine model. Oncotarget 6: 27037–27048, 2015. doi:10.18632/oncotarget.4815.
Crossref | PubMed | Google Scholar - 250. . Thyroid hormone causes mitogen-activated protein kinase-dependent phosphorylation of the nuclear estrogen receptor. Endocrinology 145: 3265–3272, 2004. doi:10.1210/en.2004-0308.
Crossref | PubMed | ISI | Google Scholar - 251. . Cutting to the chase: how matrix metalloproteinase-2 activity controls breast-cancer-to-bone metastasis. Cancers (Basel) 10: 185, 2018. doi:10.3390/cancers10060185.
Crossref | PubMed | ISI | Google Scholar - 252. . Evolution of thyroid hormone signaling in animals: non-genomic and genomic modes of action. Mol Cell Endocrinol 459: 14–20, 2017. doi:10.1016/j.mce.2017.05.019.
Crossref | PubMed | ISI | Google Scholar - 253. . Isocitrate dehydrogenase 2 suppresses the invasion of hepatocellular carcinoma cells via matrix metalloproteinase 9. Cell Physiol Biochem 37: 2405–2414, 2015. doi:10.1159/000438593.
Crossref | PubMed | Google Scholar - 254. . Tissue-specific stabilization of the thyroid hormone β1 nuclear receptor by phosphorylation. J Biol Chem 272: 4129–4134, 1997. doi:10.1074/jbc.272.7.4129.
Crossref | PubMed | ISI | Google Scholar - 255. . Hormone-activated phosphorylation of human β1 thyroid hormone nuclear receptor. Thyroid 7: 463–469, 1997. doi:10.1089/thy.1997.7.463.
Crossref | PubMed | ISI | Google Scholar - 256. . β1-Integrin-mediated neuronal responses to extracellular matrix proteins. Ann NY Acad Sci 633, 1 Glial-Neurona: 100–104, 1991. doi:10.1111/j.1749-6632.1991.tb15600.x.
Crossref | PubMed | ISI | Google Scholar - 257. . A neuronal cell line (PC12) expresses two β1-class integrins-α1β1 and α3β1-that recognize different neurite outgrowth-promoting domains in laminin. Neuron 5: 651–662, 1990. doi:10.1016/0896-6273(90)90219-6.
Crossref | PubMed | ISI | Google Scholar - 258. . ERBB2 increases metastatic potentials specifically in androgen-insensitive prostate cancer cells. PLoS One 9:
e99525 , 2014. doi:10.1371/journal.pone.0099525.
Crossref | PubMed | ISI | Google Scholar - 259. . Thyroid hormones stimulate l-arginine transport in human endothelial cells. J Endocrinol 239: 49–62, 2018. doi:10.1530/JOE-18-0229.
Crossref | PubMed | ISI | Google Scholar - 260. . Phosphorylation of thyroid hormone receptors by protein kinase A regulates DNA recognition by specific inhibition of receptor monomer binding. J Biol Chem 273: 10926–10932, 1998. doi:10.1074/jbc.273.18.10926.
Crossref | PubMed | ISI | Google Scholar - 261. . Function and interactions of integrins. Cell Tissue Res 305: 285–298, 2001. doi:10.1007/s004410100417.
Crossref | PubMed | ISI | Google Scholar - 262. . Thyroid hormone metabolism in innate immune cells. J Endocrinol 232: R67–R81, 2017. doi:10.1530/JOE-16-0462.
Crossref | PubMed | ISI | Google Scholar - 263. . MicroRNA-92a promotes vascular smooth muscle cell proliferation and migration through the ROCK/MLCK signalling pathway. J Cell Mol Med 23: 3696–3710, 2019. doi:10.1111/jcmm.14274.
Crossref | PubMed | ISI | Google Scholar - 264. . Rabbit skeletal muscle sarcoplasmic reticulum Ca2+-ATPase activity: stimulation in vitro by thyroid hormone analogues and bipyridines. Biochim Biophys Acta 1153: 184–190, 1993. doi:10.1016/0005-2736(93)90404-N.
Crossref | PubMed | ISI | Google Scholar - 265. . miR-422a inhibits cell proliferation in colorectal cancer by targeting AKT1 and MAPK1. Cancer Cell Int 17: 91, 2017. doi:10.1186/s12935-017-0461-3.
Crossref | PubMed | ISI | Google Scholar - 266. . The interplay between epithelial-mesenchymal transition (EMT) and the thyroid hormones-αvβ3 axis in ovarian cancer. Horm Cancer 9: 22–32, 2018. doi:10.1007/s12672-017-0316-3.
Crossref | PubMed | ISI | Google Scholar - 267. . C-kit and its ligand stem cell factor: potential contribution to prostate cancer bone metastasis. Neoplasia 10: 996–1003, 2008. doi:10.1593/neo.08618.
Crossref | PubMed | ISI | Google Scholar - 268. . Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164: 152–169, 2016. doi:10.1016/j.pharmthera.2016.04.009.
Crossref | PubMed | ISI | Google Scholar - 269. . Phosphorylation of the RNA-binding protein Dazl by MAPKAP kinase 2 regulates spermatogenesis. Mol Biol Cell 27: 2341–2350, 2016. doi:10.1091/mbc.e15-11-0773.
Crossref | PubMed | ISI | Google Scholar - 270. . ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis. J Clin Invest 122: 1296–1305, 2012. doi:10.1172/JCI60568.
Crossref | PubMed | ISI | Google Scholar - 271. . Integrin αvβ3 is required for cathepsin B-induced hepatocellular carcinoma progression. Mol Med Rep 11: 3499–3504, 2015. doi:10.3892/mmr.2014.3140.
Crossref | PubMed | ISI | Google Scholar - 272. . Tetraiodothyroacetic acid and tetraiodothyroacetic acid nanoparticle effectively inhibit the growth of human follicular thyroid cell carcinoma. Thyroid 20: 281–286, 2010. doi:10.1089/thy.2009.0249.
Crossref | PubMed | ISI | Google Scholar - 273. . Tetraidothyroacetic acid (tetrac) and tetrac nanoparticles inhibit growth of human renal cell carcinoma xenografts. Anticancer Res 29: 3825–3831, 2009.
PubMed | ISI | Google Scholar - 274. . Tetraiodothyroacetic acid (tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 95: 1972–1980, 2010. doi:10.1210/jc.2009-1926.
Crossref | PubMed | ISI | Google Scholar - 275. . Response of human pancreatic cancer cell xenografts to tetraiodothyroacetic acid nanoparticles. Horm Cancer 4: 176–185, 2013. doi:10.1007/s12672-013-0137-y.
Crossref | PubMed | ISI | Google Scholar - 276. . Downregulation of IDH2 exacerbates the malignant progression of osteosarcoma cells via increased NF-κB and MMP-9 activation. Oncol Rep 35: 2277–2285, 2016. doi:10.3892/or.2016.4553.
Crossref | PubMed | ISI | Google Scholar - 277. . The stem cell niches in bone. J Clin Invest 116: 1195–1201, 2006. doi:10.1172/JCI28568.
Crossref | PubMed | ISI | Google Scholar - 278. . Differential effects of the integrins α9β1, αvβ3, and αvβ6 on cell proliferative responses to tenascin. Roles of the beta subunit extracellular and cytoplasmic domains. J Biol Chem 271: 24144–24150, 1996. doi:10.1074/jbc.271.39.24144.
Crossref | PubMed | ISI | Google Scholar - 279. . Molecular components underlying nongenomic thyroid hormone signaling in embryonic zebrafish neurons. Neural Dev 4: 20, 2009. doi:10.1186/1749-8104-4-20.
Crossref | PubMed | ISI | Google Scholar - 280. . Sensory neuron sodium current requires nongenomic actions of thyroid hormone during development. J Neurophysiol 100: 2719–2725, 2008. doi:10.1152/jn.90801.2008.
Link | ISI | Google Scholar - 281. . Binding of thyroid hormone by human erythrocyte cytosol proteins. Endocr Res Commun 7: 177–188, 1980. doi:10.3109/07435808009065971.
Crossref | PubMed | Google Scholar - 282. . Partition of thyroid hormone among erythrocyte cytosol, erythrocyte membrane and human plasma binding sites. Horm Metab Res 13: 394–395, 1981. doi:10.1055/s-2007-1019279.
Crossref | PubMed | ISI | Google Scholar - 283. . Dissociable and non-dissociable cytoplasmic protein-thyroid hormone interactions. Biochim Biophys Acta 582: 332–345, 1979. doi:10.1016/0304-4165(79)90395-7.
Crossref | PubMed | Google Scholar - 284. . Integrin participates in the effect of thyroxine on plasma membrane in immature rat testis. Biochim Biophys Acta 1830: 2629–2637, 2013. doi:10.1016/j.bbagen.2012.10.022.
Crossref | PubMed | ISI | Google Scholar - 285. . MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma. J Clin Invest 127: 4179–4192, 2017. doi:10.1172/JCI91258.
Crossref | PubMed | ISI | Google Scholar - 286. . Stimulatory effects of thyroid hormone on brain angiogenesis in vivo and in vitro. J Cereb Blood Flow Metab 30: 323–335, 2010. doi:10.1038/jcbfm.2009.216.
Crossref | PubMed | ISI | Google Scholar - 287. . The molecular mechanisms of chemoresistance in cancers. Oncotarget 8: 59950–59964, 2017. doi:10.18632/oncotarget.19048.
Crossref | PubMed | Google Scholar - 288. . Functional p38 MAPK identified by biomarker profiling of pancreatic cancer restrains growth through JNK inhibition and correlates with improved survival. Clin Cancer Res 20: 6200–6211, 2014. doi:10.1158/1078-0432.CCR-13-2823.
Crossref | PubMed | ISI | Google Scholar - 289. . miR-19a-mediated downregulation of RhoB inhibits the dephosphorylation of AKT1 and induces osteosarcoma cell metastasis. Cancer Lett 428: 147–159, 2018. doi:10.1016/j.canlet.2018.04.027.
Crossref | PubMed | ISI | Google Scholar
